Ph interacting protein

ABSTRACT

The invention relates to nucleic acid molecules of a Pleckstrin Homology (PH) Domain-Interacting Protein, proteins encoded by such nucleic acid molecules; and uses of the proteins and nucleic acid molecules in the preparation of therapeutic and diagnostic agents. The proteins, nucleic acids molecules, and agents may be used in the diagnosis, prevention, and treatment of conditions and disorders involving the proteins and nucleic acid molecules including but not limited to cancer, and disorders associated with insullin response.

FIELD OF THE INVENTION

[0001] The invention relates to nucleic acid molecules of a PleckstrinHomology (PH) Domain-Interacting Protein, proteins encoded by suchnucleic acid molecules; and uses of the proteins and nucleic acidmolecules in the preparation of therapeutic and diagnostic agents. Theproteins, nucleic acids molecules, and agents may be used in thediagnosis, prevention, and treatment of conditions and disordersinvolving the proteins and nucleic acid molecules including but notlimited to cancer, and disorders associated with insulin response.

BACKGROUND OF THE INVENTION

[0002] Upon ligand stimulation of insulin receptors, insulin receptorsubstrate-1 (“IRS-1”) is rapidly phosphorylated on multiple tyrosineresidues which serve as docking sites for the assembly and activation ofSrc homology 2 (SH2) containing signaling proteins that function ineliciting many insulin-dependent biological responses (1). TheN-terminus of IRS-1 contains a PH domain followed by the structurallyhomologous phosphotyrosine binding (PTB) domain that have been shown toco-operatively contribute in mediating productive receptor/substrateinteractions (2). The PTB domain of IRS-1 binds directly tophosphorylated Tyr960 within the NPEY motif in the juxtamembrane regionof the activated insulin receptor (IR) (3). However, the exact molecularmechanism by which the PH domain promotes receptor coupling is notknown. Previous studies have demonstrated that deletion of the PH domainattenuates IRS-1 phosphorylation and subsequent insulin-mediatedmitogenesis (2). Moreover, heterologous PH domains from unrelatedproteins fail to restore mitogenic responses to insulin, suggesting thatthe IRS-1 PH domain is not simply a membrane targeting device but mayinteract with specific cellular ligands (4).

SUMMARY OF THE INVENTION

[0003] Applicants isolated a novel protein designated “PH-InteractingProtein” or “PHIP” which is a physiological ligand of IRS-1 that linksIRS-1 to the insulin receptor. Applicants have established that PHIP isa critical component of insulin-mediatedgene transcription, mitogenesis,glucose transport, and actin remodeling.

[0004] In particular, the inventors found that PHIP selectively binds tothe pleckstrin homology (PH) domain of IRS-1 in vitro, and stablyassociates with IRS-1 and IRS-2 in vivo. Overexpression of PHIP enhancedinsulin-induced transcriptional responses. By contrast, adominant-negative mutant of PHIP specifically blocked mitogenic signalselicited by insulin and inhibited insulin-induced IRS-1 tryosinephosphorylation. Furthermore, DN-PHIP prevented insulin remodeling ofthe actin cytoskeleton in L6 myoblasts, which was accompanied by aprofound inhibition of insulin-stimulated GLUT4 membrane translocation.Ectopically expressed PHIP proteins co-segregated with IRS-1 inlow-density microsomes (LDM) fractions, and modulated thephosphoserine/threonine content of IRS-1 known to be important inIRS-1/LDM interactions.Applicants are the first to identify aphysiological protein ligand of the IRS-1 PH domain, which may enhancecoupling of IRS-1 to the IR by regulating the spatialcompartmentalization and intracellular routing of IRS-1. The geneencoding PHIP was mapped to chromosome6. The present inventors alsofound that PHIP associates with STAT (Signal Transducer and Activator ofTranscription) transcription factors, in particular STAT3, and it maylink STAT transcription factors to the insulin family of receptors.Therefore, PHIP is an adaptor protein that recruits signaling moleculessuch as IRS-1 and STAT3, to activated receptors that interact with, andphosphorylate the signaling molecules.

[0005] Therefore, broadly stated the present invention provides anadaptor protein that recruits proteins of the IRS protein family andSTAT transcription factors to receptors that interact with, andphosphorylate the proteins and STAT transcription factors.

[0006] The present invention also contemplates an isolated nucleic acidmolecule encoding PHIP, including mRNAs, DNAs, cDNAs, genomic DNAs,PNAs, as well as antisense analogs and biologically, diagnostically,prophylactically, clinically or therapeutically useful variants orfragments thereof and compositions comprising same.

[0007] The invention also contemplates an isolated PHIP encoded by anucleic acid molecule of the invention, including a truncation, ananalog, an allelic or species variation thereof, a homolog of theprotein or a truncation thereof, or an activated (e.g.phosphorylated)PHIP. (PHIP and truncations, analogs, allelic or speciesvariations, homologs thereof, and activated PHIP are collectivelyreferred to herein as “PHI Proteins”). An isolated PHI Protein may beobtained from any species, particularly mammalian, including bovine,ovine, porcine, murine, equine, preferably human, from any sourcewhether natural, synthetic, semi-synthetic,or recombinant. A PHI Proteinis characterized by an N-terminal α-helical region predicting a coiledcoil structure and a region containing two bromodomains.

[0008] In accordance with an aspect of the invention an isolatedPleckstrin Homology domain Interacting Protein (“PHI Protein”) isprovided which is capable of forming a stable interaction with a PHdomain of insulin receptor substrate-1 (IRS-1), and is characterized byan N-terminal α-helical region predicting a coiled coil structure and aregion containing two bromodomains.

[0009] The nucleic acid molecules which encode for a mature PHI Proteinmay include only the coding sequence for the mature polypeptide; thecoding sequence for the mature polypeptide and additional codingsequences (e.g. leader or secretory sequences, propolypeptidesequences); the coding sequence for the mature polypeptide (andoptionally additional coding sequence) and non-coding sequence, such asintrons or non-coding sequence 5′ and/or 3′ of the coding sequence ofthe mature polypeptide.

[0010] Therefore, the term “nucleic acid molecule encoding a PHIProtein” encompasses a nucleic acid molecule which includes only codingsequence for a PHI Protein as well as a nucleic acid molecule whichincludes additional coding and/or non-coding sequences.

[0011] The nucleic acid molecules of the invention may be inserted intoan appropriate vector, and the vector may contain the necessary elementsfor the transcription and translation of an inserted coding sequence.Accordingly, vectors may be constructed which comprise a nucleic acidmolecule of the invention, and where appropriate one or moretranscription and translation elements linked to the nucleic acidmolecule.

[0012] In accordance with an aspect of the invention, a vector isprovided comprising a DNA molecule with a nucleotide sequence encodingat least one epitope of a PHI Protein, and suitable regulatory sequencesto allow expression in a host cell.

[0013] A vector can be used to transform host cells to express a PHIProtein. Therefore, the invention further provides host cells containinga vector of the invention. The invention also contemplates transgenicnon-human mammals whose germ cells and somatic cells contain a vectorcomprising a nucleic acid molecule of the invention in particular onethat encodes an analog of PHIP, or a truncation of PHIP.

[0014] A protein of the invention may be obtained as an isolate fromnatural cell sources, but it is preferably produced by recombinantprocedures. In one aspect the invention provides a method for preparinga PHI Protein utilizing the isolated nucleic acid molecules of theinvention. In an embodiment a method for preparing a PHI Protein isprovided comprising:

[0015] (a) transferring a vector of the invention comprising a nucleicacid sequence encoding a PHI Protein, into a host cell;

[0016] (b) selecting transformed host cells from untransformed hostcells;

[0017] (c) culturing a selected transformed host cell under conditionswhich allow expression of the PHI Protein; and

[0018] (d) isolating the PHI Protein.

[0019] The invention further broadly contemplates a recombinant PHIProtein obtained using a method of the invention.

[0020] A PHI Protein of the invention may be conjugated with othermolecules, such as polypeptides, to prepare fusion polypeptides orchimeric polypeptides. This may be accomplished, for example, by thesynthesis of N-terminal or C-terminal fusion polypeptides.

[0021] An aspect of the invention provides molecules (e.g. peptides)derived from a binding region of a PHI Protein.

[0022] The invention also permits the construction of nucleotide probesthat are unique to nucleic acid molecules of the invention and/or toproteins of the invention. Therefore, the invention also relates to aprobe comprising a sequence encoding a PHI Protein, or a portion (i.e.fragment) thereof. The probe may be labeled, for example, with adetectable substance and it may be used to select from a mixture ofnucleic acid molecules, a nucleic acid molecule of the inventionincluding nucleic acid molecules coding for a polypeptide which displaysone or more of the properties of a PHI Protein.

[0023] An aspect of the invention provides a complex comprising a PHIProtein or a binding region thereof, and a binding partner. In anembodiment of the invention a complex is provided comprising a PHIProtein or a PH domain binding region, and a PH domain containingprotein or a PH domain. The invention also contemplates a complexcomprising a PHI Protein or a binding region thereof, in particular anIR binding region, and a receptor that interacts with a protein of theIRS protein family, or a binding region thereof. Still further, theinvention contemplates a complex comprising a PHI Protein or a bindingregion thereof, in particular a STAT binding region, and a STATtranscription factor or a binding region thereof that interacts with aPHI Protein.

[0024] The invention further contemplates antibodies having specificityagainst an epitope of a PHI Protein or complex of the invention.Antibodies may be labeled with a detectable substance and used to detectproteins or complexes of the invention in biological samples, tissues,and cells. Antibodies may have particular use in therapeuticapplications, for example to react with tumor cells, and in conjugatesand immunotoxins as target selective carriers of various agents whichhave antitumor effects including chemotherapeutic drugs, toxins,immunological response modifiers, enzymes, and radioisotopes.

[0025] In accordance with an aspect of the invention there is provided amethod of, and products for, diagnosing and monitoring conditionsinvolving a PHI Protein by determining the presence of nucleic acidmolecules, proteins, and complexes of the invention.

[0026] The invention provides a method for identifying a substance whichbinds to a PHI Protein or a binding region thereof (e.g. a PH domainbinding region, IR binding region, or STAT binding region), comprisingreacting the protein or binding region with at least one substance whichpotentially can interact or bind with the protein or binding region,under conditions which permit the formation of complexes between thesubstance and protein or binding region, and detecting binding orrecovering complexes. Binding may be detected by assaying for complexes,for free substance, or for non-complexed protein or binding region. Theinvention also contemplates methods for identifying substances that bindto other intracellular proteins that interact with a PHI Protein orbinding region thereof. Methods can also be utilized which identifycompounds which bind to phip nucleic acid regulatory sequences (e.g.promoter sequences).

[0027] Still further the invention provides a method for evaluating atest compound for its ability to modulate the activity of a PHI Proteinof the invention. “Modulate” refers to a change or an alteration in thebiological activity of a PHI Protein of the invention. Modulation may bean increase (i.e. promotion) or a decrease (i.e. disruption) inactivity, a change in characteristics, or any other change in thebiological, functional, or immunological properties of the protein.

[0028] For example a substance which reduces or enhances the activity ofa PHI Protein may be evaluated. The association or interaction between aPHI Protein and a binding partner may be promoted or enhanced either byincreasing production of a PHI Protein, or by increasing expression of aPHI Protein, or by promoting interaction of a PHI Protein and a bindingpartner (e.g. PH domain containing protein or receptor that interactswith a protein of the IRS protein family) or by prolonging the durationof the association or interaction. The association or interactionbetween a PHI Protein and a binding partner may be disrupted or reducedby preventing production of a PHI Protein or by preventing expression ofa PHI Protein, or by preventing interaction of a PHI Protein and abinding partner or interfering with the interaction. A method mayinclude measuring or detecting various properties including the level ofsignal transduction and the level of interaction between a PHI Proteinor binding region thereof and a binding partner.

[0029] In an embodiment, the method comprises reacting a PHI Protein orbinding region thereof, with a substance which interacts with or bindsto the protein or binding region thereof and a test compound underconditions which permit the formation of complexes between the substanceand protein or binding region, and removing and/or detecting complexes.

[0030] In other embodiments, the invention provides a method foridentifying inhibitors of a PHI Protein interaction, comprising

[0031] (a) providing a reaction mixture including a PHI Protein and abinding partner, or at least a portion of each which interact;

[0032] (b) contacting the reaction mixture with one or more testcompounds;

[0033] (c) identifying compounds which inhibit the interaction of thePHI Protein and binding partner.

[0034] In certain preferred embodiments, the reaction mixture is a wholecell. In other embodiments, the reaction mixture is a cell lysate orpurified protein composition. The subject method can be carried outusing libraries of test compounds. Such agents can be proteins,peptides, nucleic acids, carbohydrates, small organic molecules, andnatural product extract libraries, such as isolated from animals,plants, fungus and/or microbes.

[0035] Still another aspect of the present invention provides a methodof conducting a drug discovery business comprising:

[0036] (a) providing one or more assay systems for identifying agents bytheir ability to inhibit or potentiate the interaction of a PHI Proteinand binding partner;

[0037] (b) conducting therapeutic profiling of agents identified in step(a), or further analogs thereof, for efficacy and toxicity in animals;and

[0038] (c) formulating a pharmaceutical composition including one ormore agents identified in step (b) as having an acceptable therapeuticprofile.

[0039] In certain embodiments, the subject method can also include astep of establishing a distribution system for distributing thepharmaceutical composition for sale, and may optionally includeestablishing a sales group for marketing the pharmaceutical preparation.

[0040] Yet another aspect of the invention provides a method ofconducting a target discovery business comprising:

[0041] (a) providing one or more assay systems for identifying agents bytheir ability to inhibit or potentiate the interaction of a PHI Proteinand binding partner,

[0042] (b) (optionally) conducting therapeutic profiling of agentsidentified in step (a) for efficacy and toxicity in animals; and

[0043] (c) licensing, to a third party, the rights for further drugdevelopment and/or sales for agents identified in step (a), or analogsthereof.

[0044] Compounds which modulate the biological activity of a PHI Proteinmay also be identified using the methods of the invention by comparingthe pattern and level of expression of a nucleic acid molecule orprotein of the invention in biological samples, tissues and cells, inthe presence, and in the absence of the test compounds.

[0045] Methods are also contemplated that identify compounds orsubstances (e.g. polypeptides) which interact with phip regulatorysequences (e.g. promoter sequences, enhancer sequences, negativemodulator sequences).

[0046] The disruption or promotion of the interaction between themolecules in complexes of the invention may be useful in therapeuticprocedures. Therefore, the invention features a method for treating asubject having a condition characterized by an abnormality in a signaltransduction pathway involving an interaction between a PHI Protein or aPH domain binding region, and a PH domain containing protein or a PHdomain; an interaction between an IR binding region and a receptor thatinteracts with a protein of the IRS protein family; or, an interactionbetween a PHI Protein or a STAT binding region, and a STAT transcriptionfactor or a binding region thereof that interacts with a PHI Protein.

[0047] The nucleic acid molecules, proteins, complexes, peptides, andantibodies of the invention, and substances, agents, and compoundsidentified using the methods of the invention, may be used to modulatethe biological activity of a PHI Protein or complex of the invention, ora signal transduction pathway involving a PHI Protein or complex of theinvention, and they may be used in the treatment of conditions mediatedby a PHI Protein or a signal transduction pathway involving a PHIProtein or complex of the invention. Accordingly, the nucleic acidmolecules, proteins, antibodies, complexes of the invention, andsubstances, agents, and compounds may be formulated into compositionsfor administration to individuals suffering from one or more of theseconditions. In an embodiment of the invention the condition is cancer.In another embodiment of the invention the condition is a disorderassociated with an insulin response. Therefore, the present inventionalso relates to a composition comprising one or more of a protein,antibody, complex, or nucleic acid molecule of the invention, orsubstance, compound, or agent identified using the methods of theinvention, and a pharmaceutically acceptable carrier, excipient ordiluent. A method for treating or preventing these conditions is alsoprovided comprising administering to a patient in need thereof acomposition of the invention.

[0048] The invention also contemplates the use of a nucleic acidmolecule, protein, complex, peptide, antibody, substance, agent, orcompound of the invention in the preparation of a medicament for thetreatment of a condition or disorder mediated by a PHI Protein or asignal transduction pathway involving a PHI Protein or a complex of theinvention.

[0049] In accordance with a further aspect of the invention, there areprovided processes for utilizing proteins, complexes, or nucleic acidmolecules described herein, for in vitro purposes related to scientificresearch, synthesis of DNA and manufacture of vectors.

[0050] Other features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.These and other aspects, features, and advantages of the presentinvention should be apparent to those skilled in the art from thefollowing drawings and detailed description.

DESCRIPTION OF THE DRAWINGS

[0051] The invention will now be described in relation to the drawingsin which:

[0052]FIG. 1 show the deduced amino-acid sequence and schematicrepresentation of PHIP. (A) Alignment of mouse (m) and human (h) PHIPsequences. (B) There are two bromodomains in PHIP, BD1 (230-345) and BD2(387-503). The PHIP IRS-1/PH binding region (PBR) (amino acids 8-209)isolated from the yeast clone VP1.32 is underlined.

[0053]FIG. 2 are blots showing that PHIP associates with IRS-1 both invitro and in vivo. (A) PHIP migrates with an apparent molecular mass of104 kDa. PHIP was immunoprecipitated from multiple myeloma U266 celllysates and immunoblotted with anti-PHIP antibodies (Abs) (10) (B) Twoforms of PHIP (97 and 104 KDa) observed in anti-PHIP immunoprecipitatesfrom cell lysates of U266, human A431 epidermoid carcinoma, Rat-2 andmouse NIH/3T3 fibroblasts. (C) PHIP interacts selectively with the IRS-1PH domain in vitro. Yeast cell lysates expressing HA-tagged PH domainsfrom either IRS-1, SOS1, ECT-2 or Ras-GAP (GAP) were mixed withimmobilized GST-PHIP fusion proteins and complexes were subjected toWestern blot analysis with anti-HA Abs (13). (D) Binding of IRS-1 PHdomain mutants to PHIP. Left, Immunodetection of HA-tagged IRS-1 PHdomain mutants from whole cell lysates (50 μg) of transientlytransfected COS-1 cells. PH^(WT) (IRS-1 PH domain residues3-133),PH^(NT) (residues 3-67), PH^(CT) (residues 55-133), PH^(W106A) (Trp106residue conserved in all PH domains changed to Ala); Right cell lysates(500 μg) expressing the indicated IRS-1 PH domain mutant were mixed witheither GST or GST-PHIP (PBR) proteins and processed as in (C). (E) PHIPstably associates with IRS-1 in vivo. Serum deprived NIH/IR cells wereeither left unstimulated or stimulated with insulin (2 μM) for 5minutes. Cell lysates were immunoprecipitated with anti-IRS-1^(PCT)(Upstate Biotechnology Inc.,UBI), anti-IRS-1 ^(PH) or anti-PHIP Abs andsubjected to western blotting with anti-PHIP or anti-IRS-1^(PCT) Abs asindicated. Anti-IRS-2Abs were used to coimmunoprecipitateIRS-2/PHIPcomplexes from asynchronized cells. (F) PHIP is not a substrate of theIR. PHIP was immunoprecipitated from untreated and insulin-treated humankidney 293 cell extracts using anti-PHIP Abs directed against the PBRregion. Immune complexes were resolved by SDS-PAGE and immunoblottedwith anti-phosphotyrosine Abs (anti-pTyr, PY20, New England Biolabs).The blot was stripped and reprobed with either anti-IRS-1^(PCT) oranti-PHIP Abs. A 103 KDa phosphoprotein denoted by an asterisk likelyrepresents STAT3.

[0054]FIG. 3 are graphs showing the effect of PHIP on insulin signaling.(A) Human PHIP potentiates transcription of 5×SRE-fos luciferaseexpression by insulin. COS-1 cells were transiently transfected withincreasing amounts of pCGN/hPHIP (6 μg, 9 μg, 12 μg) or empty vector ascontrol (12 μg) together with 3 μg of 5×SRE-fos luciferase reporterconstruct (5×SRE-LUC). Serum-starved cells were either left untreated ortreated with Mek-1 inhibitor (50 μM) for 2 hours. Cells were incubatedfor 10 hours with or without insulin (0.2 μM) and relative luciferaseactivity was measured in cell lysates using a dual-light system (Tropix)(16). Results are expressed as the mean+SD of triplicates from arepresentative experiment (B) IRS-1 PH domain inhibits PHIP-inducedSRE-LUC activity. COS cells were cotransfected with pCGN/hPHIP (4 μg)and the indicated amount of pCGN/IRS-1 PH together with 2 μg of5×SRE-LUC. Cells were insulin treated and processed as in (A). C) IRS-1PH mediated inhibition of PHIP-stimulated luciferase activity isrestored by wild-type IRS-1 in a dose-dependent manner. COS cells werecotransfected with 1 μg of pCGN/hPHIP, 2 μg of 5×SRE-LUC, either 1 μg ofpCGN/IRS-1-PH or vector DNA and increasing amounts of pCGN/IRS-1 cDNA asindicated. Cells were then insulin treated and processed as in (A).

[0055]FIG. 4 shows blots illustrating the dominant negative PHIPinhibits insulin-induced tyrosine phosphorylation of IRS-1. (A,B) COS-7cells were transiently transfected with either pCGN/HA-DN-PHIP(DN/PHIP), pCGN/HA-PHIP (PHIP) or empty vector. Cell cultures weretreated with or without insulin (0.2 μM) for 5 minutes. Whole celllysates or anti-IRS-1 immunoprecipitates were subjected to immunoblotanalysis with either anti-IRS 1PCT, anti-pTyr or anti-HA Abs asindicated. Anti-IR immunoprecipitates were blotted with anti-pTyrantibodies. The membrane was stripped and reprobed with anti-IRantibodies. (C) Rat-1 fibroblasts were transiently transfected witheither pCGN/HA-DN-PHIP or empty vector. Cell cultures were treated withinsulin (0.2 μM) for 5 minutes. Cell lysates were precipitated withanti-IRS-1PCT or anti-Shc Abs and were subjected to immunoblot analysiswith anti-pTyr Abs. The membrane containing Shc immune complexes wasstripped and reprobed with anti-Shc Abs. (D) DN/PHIP inhibits MAPKactivity through IRS-1 and not SHC adaptor protein. COS cells weretransiently transfected with pCDNA1/HA-p44MAPK and eitherpCGN/HA-DN-PHIP or empty vector. Cell cultures were treated with orwithout insulin. Cell lysates were precipitated with anti-HA Abs andsubjected to an in-vitro kinase assay with MBP as substrate. TheHA-depleted lysates were then precipitated with anti-Shc Abs andsubjected to analysis with anti-pTyr Abs.

[0056]FIG. 5 shows PHIP oveexpression altos IRS-1 electrophoreticmobility (A) PHIP and IRS-1 are co-localized in the LDM. LDM andcytosolic fractions were prepared from unstimulated andinsulin-stimulated COS-7 cells transiently transfected with 20 μg ofpCGN/hPHIP (Human PHIP) or empty vector as control. Two hundredmicrogram of protein from each fraction is resolved by SDS-PAGE andanalyzed by immunoblotting using anti-IRS-1^(PCT) antibodies (Abs).Anti-phosphotyrosine(pTyr) and Anti-HA Abs are used to detectinsulin-induced tyrosine phosphorylated IRS-1 and ectopically expressedPHIP, respectively. Anti-transferrin receptor Abs are used as the markerfor the LDM compartment (B) PHIP regulates IRS-1 subcellularlocalization by regulating IRS-1 serine/threonine phosphorylation.Western blot analysis using anti-IRS-1^(PCT) Abs were performed on COS-7cell lysates transiently transfected with empty vector (20 μg), andplasmid expressing HA-tagged hPHIP (5 μg, 10 μg, and 20 μg). EctopichPHIP expression was monitored using anti-HA Abs.

[0057]FIG. 6 is a schematic representation of PHIP and neuronaldifferentiation related protein (NDRP). There are two bromodomains inPHIP, BD1 (230-345) and BD2 (387-503). The PHIP/IRS-1 PH binding region(PBR) (amino-acids 5-209) is underlined.

[0058]FIG. 7 shows an amino acid sequence alignment of human and mouseneuronal differentiation related protein (NDRP).

[0059]FIG. 8 shows a nucleic acid sequence alignment of human and mouseneuronal differentiation related protein (NDRP).

[0060]FIG. 9 shows an amino acid sequence alignment of WD-Repeat Protein9 and PHIP.

[0061]FIG. 10 shows a nucleic acid sequence alignment of WD-RepeatProtein 9 and PHIP.

DETAILED DESCRIPTION OF THE INVENTION

[0062] In accordance with the present invention there may be employedconventionalmolecular biology, microbiology, and recombinant DNAtechniques within the skill of the art Such techniques are explainedfully in the literature. See for example, Sambrook, Fritsch, & Maniatis,Molecular Cloning: A Laboratory Manual, Second Edition (1989) ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); DNA Cloning:A Practical Approach, Volumes I and II (D. N. Glover ed. 1985);Oligonucleotide Synthesis (M. J. Gait ed. 1984); Nucleic AcidHybridization B. D. Hames & S. J. Higgins eds. (1985); Transcription andTranslation B. D. Hames & S. J. Higgins eds (1984); Animal Cell CultureR. I. Freshney, ed. (1986); Immobilized Cells and enzymes IRL Press,(1986); and B. Perbal, A Practical Guide to Molecular Cloning (1984).

[0063] 1. Glossary

[0064] The term “agonist” of a protein of interest, for example, a PHIProtein, refers to a compound that binds the protein or part thereof andmaintains or increases the activity of the protein to which it binds.Agonists may include proteins, nucleic acids, carbohydrates, or anyother molecules that bind to a protein, complex, or molecule of thecomplex (e.g. PHI Protein). Agonists also include a molecule (e.g.peptide) derived from a PHI Protein or binding region thereof (e.g. PHbinding domain region, IR binding region, or STAT binding region) butwill not include the full length sequence of the wild-type molecule.Peptide mimetics, synthetic molecules with physical structures designedto mimic structural features of particular peptides, may serve asagonists. The stimulation may be direct, or indirect, or by acompetitive or non-competitive mechanism.

[0065] The term “antagonist”, as used herein, of a protein of interest,for example, a PHI Protein, refers to a compound that binds the proteinor part thereof, but does not maintain the activity of the protein towhich it binds. Antagonists may include proteins, nucleic acids,carbohydrates, or any other molecules that bind to a protein, complex,or molecule of the complex (e.g. PHI Protein). Antagonists also includea molecule (e.g. peptide) derived from a PHI Protein or binding regionthereof (e.g. PH binding domain region, IR binding region, or STATbinding region) but preferably will not include the full length sequenceof the wild-type molecule. Peptide mimetics, synthetic molecules withphysical structures designed to mimic structural features of particularpeptides, may serve as antagonists. The inhibition may be direct, orindirect, or by a competitive or non-competitive mechanism.

[0066] “Antibody” includes intact monoclonal or polyclonal molecules,and immunologically active fragments (e.g. a Fab or (Fab)₂ fragment), anantibody heavy chain, humanized antibodies, and antibody light chain, agenetically engineered single chain F_(v) molecule (Ladner et al, U.S.Pat. No. 4,946,778), or a chimeric antibody, for example, an antibodywhich contains the binding specificity of a murine antibody, but inwhich the remaining portions are of human origin. Antibodies includingmonoclonal and polyclonal antibodies, fragments and chimeras, may beprepared using methods known to those skilled in the art. Antibodiesthat bind a protein, complex, or peptide of the invention can beprepared using intact proteins, peptides or fragments containing animmunizing antigen of interest. The polypeptide or oligopeptide used toimmunize an animal may be obtained from the translation of RNA orsynthesized chemically and can be conjugated to a carrier protein, ifdesired. Suitable carriers that may be chemically coupled to proteins orpeptides include bovine serum albumin and thyroglobulin, keyhole limpethemocyanin. The coupled protein or peptide may then be used to immunizethe animal (e.g., a mouse, a rat, or a rabbit).

[0067] A “binding region” is that portion of a PHI Protein or moleculein a complex of the invention which interacts with or binds directly orindirectly with another molecule (e.g. PH domain or STAT3) or withanother molecule in a complex of the invention. The binding domain maybe a sequential portion of the molecule i.e. a contiguous sequence ofamino acids, or it may be conformational i.e. a combination ofnon-contiguous sequences of amino acids which when the molecule is inits native state forms a structure that interacts with another moleculein a complex of the invention.

[0068] The term “complementary” refers to the natural binding of nucleicacid molecules under permissive salt and temperature conditions bybase-pairing. For example, the sequence “A-G-T” binds to thecomplementary sequence “T-C-A”. Complementarity between twosingle-stranded molecules may be “partial”, in which only some of thenucleic acids bind, or it may be complete when total complementarityexists between the single stranded molecules.

[0069] By being “derived from” a binding region is meant any molecularentity which is identical or substantially equivalent to the nativebinding region of a PHI Protein or a molecule in a complex of theinvention. A peptide derived from a specific binding region mayencompass the amino acid sequence of a naturally occurring binding site,any portion of that binding site, or other molecular entity thatfunctions to bind to an associated molecule. A peptide derived from sucha binding region will interact directly or indirectly with an associatedmolecule in such a way as to mimic the native binding region. Suchpeptides may include competitive inhibitors, peptide mimetics, and thelike.

[0070] “Interaction” or “interacting” means any physical associationbetween proteins, other molecules such as lipids, carbohydrates,nucleotides, and other cell metabolites, which may be covalent ornon-covalent (e.g. electrostatic bonds, hydrogen bonds, and Van derWaals bonds). Interactions include interactions between proteins andcellular molecules, including protein-protein interactions,protein-lipid interactions, and others. Certain interacting moleculesinteract only after one or more of them have been stimulated. Forexample, a PH domain containing protein may only bind to a ligand if theprotein is phosphorylated. Interactions between proteins and othercellular molecules may be direct or indirect. An example of an indirectinteraction is the independent production, stimulation, or inhibition ofa PHI Protein or binding domain thereof, by a modulator. Various methodsknown in the art may be used to measure the level of an interaction.

[0071] “IR binding region” refers to a binding region of a PHI Proteinof the invention that interacts with or binds a receptor that interactswith a protein of the IRS protein family. In preferred embodiments theinteraction is specific and a binding region does not interact, orinteracts to a lesser extent with molecules that are not such receptors.The K_(d) for an interaction between an IR binding region and a receptoris preferably less than 10 μM, more preferably 1,000 nM, most preferably500 nM. In embodiments of the invention, an IR binding region may beprovided as part of a protein, alone or in isolation from the remainderof the amino acid sequence of the protein, or contained in a lipidvesicle or as a freely soluble small molecule. An example of an IRbinding region is the region corresponding to bromodomain BD1 comprisingamino acids 230-345 of SEQ. ID. NO. 2 or 5, or the amino acid sequenceof SEQ.ID. NO. 15, or bromodomain BD2 comprising amino acids 387-503 ofSEQ. ID. NO. 2 or 5, or the amino acid sequence of SEQ.ID. NO. 17.

[0072] “IRS protein family” refers to docking proteins that provide aninterface between multiple receptor complexes and various signalingproteins with Src homology 2 domains. The proteins are involved insignaling events initiated by several classes of receptors including theinsulin receptor, growth factor receptors (e.g. insulin-like growthfactor I (IGF-I) receptor, receptors for growth hormone and prolactin),cytokine receptors (e.g. receptors for IL-2, IL-4, IL-9, IL-13, andIL-15, members of the IL-6 receptor family), and interferon receptors(e.g. receptors for IFNα/β and IFNγ). The insulin receptor substrate,IRS-1 is the prototype for this class of molecules. Other members of thefamily include IRS-2, Gab-1, and p62^(dok). The proteins contain severalcommon structures including an NH₂-terminal PH domain and/orphosphotyrosine binding (PTB) domain that mediate protein-proteininteractions; multiple COOH-terminal tyrosine residues that bindSH2-containing proteins; proline-rich regions to interact with SH3 or WWdomains; and serine/threonine-rich regions which regulate intracellularlocalization/trafficking of IRS proteins likely through protein-proteininteractions (M. F. White and L. Yenush, 1998 and references therein).IRS-1 and IRS-2 have a PH domain at the extreme NH₂ terminus, followedimmediately by a PTB domain that binds to phosphorylated NPXY motifs. Anactivated i.e. phosphorylated protein of the IRS protein family may beused for purposes of the invention.

[0073] “Peptide mimetics” are structures which serve as substitutes forpeptides in interactions between molecules (See Morgan et al (1989),Ann. Reports Med. Chem. 24:243-252 for a review). Peptide mimeticsinclude synthetic structures which may or may not contain amino acidsand/or peptide bonds but retain the structural and functional featuresof a peptide, or agonist or antagonist of the invention. Peptidemimetics also include peptoids, oligopeptoids (Simon et al (1972) Proc.Natl. Acad, Sci USA 89:9367); and peptide libraries containing peptidesof a designed length representing all possible sequences of amino acidscorresponding to a peptide, or agonist or antagonist of the invention.

[0074] A “PH domain” refers to a distinct approximately 100 amino acidregion originally identified in pleckstrin but are known to occur inmany signaling proteins M. F. White and L. Yenush, 1998 and referencestherein). The PH domain has a distinct structural module characterizedby two anti-parallel β sheets forming a sandwich, with one cornercovered by an amphipathicCOOH-terminal α-helix (Lemmon et al, 1996, Cell85:621-624). PH domains may be identified using sequence alignmenttechniques and three-dimensional structure comparisons. Preferred PHdomains are the PH domains of proteins of the IRS protein family,preferably IRS-1 and IRS-2 PH domains. In embodiments of the invention,a PH domain may be provided as part of a protein, alone or in isolationfrom the remainder of the amino acid sequence of the protein, orcontained in a lipid vesicle or as a freely soluble small molecule.

[0075] “PH domain binding region” refers to a binding region of a PHIProtein that interacts with or binds a PH domain. In preferredembodiments the interaction is specific and a binding region does notinteract, or interacts to a lesser extent with molecules that are non-PHdomains. The K_(d) for an interaction between a PH domain binding regionand a PH domain is preferably less than 10 μM, more preferably 1,000 nM,most preferably 500 nM. In embodiments of the invention, a PH domainbinding region may be provided as part of a protein, alone or inisolation from the remainder of the amino acid sequence of the protein,or contained in a lipid vesicle or as a freely soluble small molecule.An example of a PH domain binding region is the PH domain binding regioncorresponding to amino acids 8 to 209 in SEQ. ID. NO. 2, 5, 8, or 10 orthe amino acid sequence of SEQ. ID. NO. 12 or 13 (referred to herein as“PH binding region” or “BR”).

[0076] A “PH domain containing protein” refers to proteins or peptides,or parts thereof which comprise or consist essentially of a PH domain.In embodiments of the invention, a PH domain containing protein may beprovided as part of a protein, alone or in isolation from the remainderof the amino acid sequence of the protein, or contained in a lipidvesicle or as a freely soluble small molecule. Examples of such proteinsinclude proteins of the IRS protein family, preferably IRS-1 and IRS-2.

[0077] A “receptor that interacts with a protein of the IRS proteinfamily” refers to receptor tyrosine kinases and cytokine receptors thatinteract with, and phosphorylate a protein of the IRS protein family.Examples of these receptors include the insulin receptor, growth factorreceptors (e.g. insulin-like growth factor I (IGF-I) receptor, receptorsfor growth hormone and prolactin), cytokine receptors (e.g. receptorsfor IL-2, IL-4, IL-9, IL-13, and IL-15, members of the IL-6 receptorfamily), and interferon receptors (e.g. receptors for IFNα/β and IFNγ).Preferably,the invention uses the insulin receptor (“IR”) andinsulin-like growth factor I receptor (“IGF-1R”).

[0078] The terms “sequence similarity” or “sequence identity” refer tothe relationship between two or more amino acid or nucleic acidsequences, determined by comparing the sequences, which relationship isgenerally known as “homology”. Identity in the art also means the degreeof sequence relatedness between amino acid or nucleic acid sequences, asthe case may be, as determined by the match between strings of suchsequences. Both identity and similarity can be readily calculated(Computational Molecular Biology, Lesk, A. M., ed., Oxford UniversityPress New York, 1988; Biocomputing: Informatics and Genome Projects,Smith, D. W. ed., Academic Press, New York, 1993; Computer Analysis ofSequence Data, Part I Griffin, A. M., and Griffin, H. G. eds. HumanaPress, New Jersey, 1994; Sequence Analysis in Molecular Biology, vonHeinje, G., Academic Press, New York, 1987; and Sequence AnalysisPrimer, Gribskov, M. and Devereux, J., eds. M. Stockton Press, New York1991). While there are a number of existing methods to measure identityand similarity between two amino acid sequences or two nucleic acidsequences, both terms are well known to the skilled artisan (SequenceAnalysis in Molecular Biology, von Heinje, G., Academic Press, New York,1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds. M.Stockton Press, New York, 1991; and Carillo, H., and Lipman, D. SIAM J.Applied Math., 48:1073, 1988). Preferred methods for determiningidentity are designed to give the largest match between the sequencestested. Methods to determine identity are codified in computer programs.Preferred computer program methods for determining identity andsimilarity between two sequences include but are not limited to the GCGprogram package (Devereux, J. et al, Nucleic Acids Research 12(1): 387,1984), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec. Biol.215:403, 1990). Identity or similarity may also be determined using thealignment algorithm of Dayhoff et al [Methods in Enzymology 91: 524-545(1983)].

[0079] “Signal transduction pathway” refers to the sequence of eventsthat involves the transmission of a message from an extracellularprotein to the cytoplasm through the cell membrane. Signal transductionpathways contemplated herein include pathways involving a PHI Protein ora complex of the invention or an interacting molecule thereof Inparticular, the pathways are those involving the IRS protein family, inparticular IRS-1, or a STAT transcription factor (e.g. STAT3) thatregulate cellular processes including the control of glucose metabolism,protein synthesis, and cell survival, growth, and transformation. Suchpathways include the MAP kinase pathway leading to c-fos geneexpression; IRS-1 regulated IL-4 stimulation of hematopoietic cells; andIRS-1 mediated GH and interferon γ (FNγ) signaling. IRS-1 also mediatespathways dependent on phosphatidylinositol3-linase. In addition, IRSproteins regulate cellular processes through IGR-I/IGF-R signalingpathways which when activated stimulate mitogenesis and cellulartransformation, and inhibit apoptosis. The amount and intensity of agiven signal in a signal transduction pathway can be measured usingconventional methods (See Example 1 herein). For example, theconcentration and localization of various proteins and complexes in asignal transduction pathway can be measured, conformational changes thatare involved in the transmission of a signal may be observed usingcircular dichroism and fluorescence studies, and various symptoms of acondition associated with an abnormality in the signal transductionpathway may be detected.

[0080] “STAT transcription factor” or “STAT” refers to a member of thefamily of proteins required for cytokine-mediated signal transductionand immune function (Schindler et al., Ann. Rev. Biochem. 64: 621-651,1995). Following receptor ligation by cytokines, STAT family membersbecome activated by tyrosine phosphorylation, through the action ofJanus family kinase (JAK) members. Activated STAT proteins formhomodimeric and heterodimeric complexes that translocate from thecytoplasm to the nucleus where they bind to cis-acting promotersequences and regulate transcription of a number of genes required forthe immune response. Examples of STAT transcriptional factors includebut are not limited to STAT1 (α and β), STAT3 (α and β), STAT4, andSTAT6, and all isoforms, and homo- and heterodimers thereof, preferablySTAT3 (α and β). STAT3 activation is required for IL-6 dependentresponses associated with tissue inflammation, and IL-10 responses areassociated with Th2 helper cell function (Inoue, M. et al J. Biol Chem.272: 9550-9555, 1975 and Weber-North et al, J. Biol. Chem. 271: 27954,1996)

[0081] “STAT binding region” refers to a binding region of a PHI Proteinthat interacts with a STAT transcription factor. In preferredembodiments the interaction is specific and a binding region does notinteract, or interacts to a lesser extent with molecules that arenon-STAT transcription factors. The K_(d) for an interaction between aPHI Protein and a STAT transcription factor is preferably less than 10μM, more preferably 1,000 nM, most preferably 500 nM. In embodiments ofthe invention, a STAT binding region may be provided as part of aprotein, alone or in isolation from the remainder of the amino acidsequence of the protein, or contained in a lipid vesicle or as a freelysoluble small molecule

[0082] 2. Nucleic Acid Molecules

[0083] As hereinbefore mentioned, the invention provides an isolatednucleic acid molecule comprising or consisting essentially of a sequenceencoding a PHI Protein. The term “isolated” refers to a nucleic acid (orprotein) removed from its natural environment, purified or separated, orsubstantially free of cellular material or culture medium when producedby recombinant DNA techniques, or chemical reactants, or other chemicalswhen chemically synthesized. Preferably, an isolated nucleic acid is atleast 60% free, more preferably at least 75% free, and most preferablyat least 90% free from other components with which it is naturallyassociated. The term “nucleicacid” is intended to include modified orunmodified DNA, RNA, including mRNAs, DNAs, cDNAs, and genomic DNAs, ora mixed polymer, and can be either single-stranded, double-stranded ortriple-stranded. For example, a nucleic acid sequence may be asingle-stranded or double-stranded DNA, DNA that is a mixture ofsingle-and double-stranded regions, or single-, double- andtriple-stranded regions, single- and double-stranded RNA, RNA that maybe single-stranded, or more typically, double-stranded, ortriple-stranded, or a mixture of regions comprising RNA or DNA, or bothRNA and DNA. The strands in such regions may be from the same moleculeor from different molecules. The DNAs or RNAs may contain one or moremodified bases. For example,the DNAs or RNAs may have backbones modifiedfor stability or for other reasons. A nucleic acid sequence includes anoligonucleotide, nucleotide, or polynucleotides. The term “nucleic acidmolecule” and in particular DNA or RNA refers only to the primary andsecondary structure and it does not limit it to any particular tertiaryforms.

[0084] In accordance with an aspect of the invention, an isolatednucleic acid molecule is provided of at least 30 nucleotides whichhybridizes to one of SEQ ID NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34or the complement of one of SEQ ID NO. 1, 4, 7, 9, 11, 14, 16, or 18through 34 under stringent hybridization conditions.

[0085] In an embodiment of the invention an isolated nucleic acidmolecule is contemplated which comprises:

[0086] (i) a nucleic acid sequence encoding a protein having substantialsequence identity with an amino acid sequence of SEQ. ID. NO. 2, 3, 5,6, 8, 10, 12, 13, 15, or 17;

[0087] (ii) a nucleic acid sequence complementary to (i);

[0088] (iii) a nucleic acid sequence differing from any of (i) or (ii)in codon sequences due to the degeneracy of the genetic code;

[0089] (iv) a nucleic acid sequence comprising at least 10, preferablyat least 15, more preferably at least 18, most preferably at least 20nucleotides capable of hybridizing to a nucleic acid sequence of one ofSEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34 or to a degenerateform thereof;

[0090] (v) a nucleic acid sequence encoding a truncation, an analog, anallelic or species variation of a protein comprising the amino acidsequence of SEQ. ID. NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17; or

[0091] (vi) a fragment, or allelic or species variation of (i), (ii) or(iii)

[0092] In a specific embodiment, the isolated nucleic acid moleculecomprises:

[0093] (i) a nucleic acid sequence having substantial sequence identityor sequence similarity with a nucleic acid sequence of one of SEQ. ID.NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34;

[0094] (ii) nucleic acid sequences comprising the sequence of one ofSEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34 wherein T can alsobe U;

[0095] (iii) nucleic acid sequences complementary to (i), preferablycomplementary to the full nucleic acid sequence of one of SEQ. ID. NO.1, 4, 7, 9, 11, 14, 16, or 18 through 34;

[0096] (iv) nucleic acid sequences differing from any of the nucleicacid sequences of (i), (ii), or (iii) in codon sequences due to thedegeneracy of the genetic code; or

[0097] (v) a fragment, or allelic or species variation of (i), (ii) or(iii).

[0098] In a preferred embodiment the isolated nucleic acid comprises anucleic acid sequence encoded by the amino acid sequence of SEQ. ID. NO.2, 3, 5, 6, 8, 10, 12, 13, 15, or 17, or comprises the nucleic acidsequence of one of SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34wherein T can also be U. In another embodiment, the isolated nucleicacid comprises a nucleic acid sequence encoding the amino acid sequenceof SEQ. ID. NO. 71, 73, 75 or 77 or comprises the nucleic acid sequenceof SEQ. ID. NO. 70, 72, 74 or 76 wherein T can also be U.

[0099] Preferably, the nucleic acid molecules of the present inventionhave substantial sequence identity using the preferred computer programscited herein, for example greater than 50% nucleic acid identity;preferably greater than 60% nucleic acid identity; and more preferablygreater than 65%, 70%, 75%, 80%, or 85% sequence identity, mostpreferably at least 95%, 96%, 97%, 98%, or 99% sequence identity to thesequence of one of SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, or 18 through34.

[0100] Isolated nucleic acids encoding a PHI Protein, or part thereofand comprising a sequence that differs from the nucleic acid sequence ofone of SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, or 18 through 34, due todegeneracy in the genetic code are also within the scope of theinvention. Such nucleic acids encode equivalent proteins. As oneexample, DNA sequence polymorphisms within a nucleic acid molecule ofthe invention may result in silent mutations that do not affect theamino acid sequence. Variations in one or more nucleotides may existamong individuals within a population due to natural allelic variation.Any and all such nucleic acid variations are within the scope of theinvention. DNA sequence polymorphisms may also occur which lead tochanges in the amino acid sequence of a PHI Protein. These amino acidpolymorphisms are also within the scope of the present invention. Inaddition, species variations i.e. variations in nucleotide sequencenaturally occurring among different species, are within the scope of theinvention.

[0101] Another aspect of the invention provides a nucleic acid moleculewhich hybridizes under selective conditions, (e.g. high stringencyconditions), to a nucleic acid which comprises a sequence which encodesa PHI Protein, or part thereof. The sequence preferably encodes theamino acid sequence of SEQ. ID. NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17and comprises at least 10, 15, 18, 20, 25, 30, 35, 40, 45 nucleotides,more typically at least 50 to 200 nucleotides. Selectivity ofhybridization occurs with a certain degree of specificity rather thanbeing random. Appropriate stringency conditions which promote DNAhybridization are known to those skilled in the art, or can be found inCurrent Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989),6.3.1-6.3.6. For example,5.0 to 6.0×sodium chloride/sodium citrate (SSC)or 0.5% SDS at about 45° C., followed by a wash of 2.0×SSC at 50° C. maybe employed. The stringency may be selected based on the conditions usedin the wash step. By way of example, the salt concentration in the washstep can be selected from a high stringency of about 0.2×SSC at 50° C.In addition, the temperature in the wash step can be at high stringencyconditions, at about 65° C.

[0102] It will be appreciated that the invention includes nucleic acidmolecules encoding a PHI Protein, including truncations of the proteins,allelic and species variants, and analogs of the proteins as describedherein. In particular, fragments of a nucleic acid of the invention arecontemplated that are a stretch of at least 10, 15, 18, 20, 25, 30, 35,40, or 45 nucleotides, more typically at least 50 to 200 nucleotides butless than 2 kb. In an embodiment fragments are provided comprisingnucleic acid sequences encoding a binding region of a PHI Protein, forexample, the PH domain binding region (e.g. SEQ ID NO. 11), or IRbinding region (e.g. SEQ ID NO. 14 or 16). It will further beappreciated that variant forms of the nucleic acid molecules of theinvention which arise by alternative splicing of an mRNA correspondingto a cDNA of the invention are encompassed by the invention.

[0103] An isolated nucleic acid molecule of the invention whichcomprises DNA can be isolated by preparing a labeled nucleic acid probebased on all or part of the nucleic acid sequence of SEQ. ID. NO. 1, 4,7, 9, 11, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, or 34. The labeled nucleic acid probe is used to screen anappropriate DNA library (e.g. a cDNA or genomic DNA library). Forexample, a cDNA library can be used to isolate a cDNA encoding a PHIProtein, by screening the library with the labeled probe using standardtechniques. Alternatively, a genomic DNA library can be similarlyscreened to isolate a genomic clone encompassing a phip gene. Nucleicacids isolated by screening of a cDNA or genomic DNA library can besequenced by standard techniques.

[0104] An isolated nucleic acid molecule of the invention that is DNAcan also be isolated by selectively amplifying a nucleic acid of theinvention. “Amplifying” or “amplification” refers to the production ofadditional copies of a nucleic acid sequence and is generally carriedout using polymerase chain reaction (PCR) technologies well known in theart (Dieffenbach, C. W. and G. S. Dveksler (1995) PCR Primer, aLaboratory Manual, Cold Spring Harbor Press, Plainview, N.Y.). Inparticular, it is possible to design synthetic oligonucleotide primersfrom the nucleotide sequence of SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34 foruse in PCR. A nucleic acid can be amplified from cDNA or genomic DNAusing these oligonucleotide primers and standard PCR amplificationtechniques. The nucleic acid so amplified can be cloned into anappropriate vector and characterized by DNA sequence analysis. cDNA maybe prepared from mRNA, by isolating total cellular mRNA by a variety oftechniques, for example, by using the guanidinium-thiocyanate extractionprocedure of Chirgwin et al., Biochemistry, 18, 5294-5299 (1979). cDNAis then synthesized from the mRNA using reverse transcriptase (forexample, Moloney MLV reverse transcriptase available from Gibco/BRL,Bethesda, Md., or AMV reverse transcriptase available from SeikagakuAmerica, Inc., St. Petersburg, Fla.).

[0105] An isolated nucleic acid molecule of the invention which is RNAcan be isolated by cloning a cDNA encoding a PHI Protein, into anappropriate vector which allows for transcription of the cDNA to producean RNA molecule which encodes a PHI Protein. For example, a cDNA can becloned downstream of a bacteriophage promoter, (e.g. a T7 promoter) in avector, cDNA can be transcribed in vitro with T7 polymerase, and theresultant RNA can be isolated by conventional techniques.

[0106] Nucleic acid molecules of the invention may be chemicallysynthesized using standard techniques. Methods of chemicallysynthesizing polydeoxynucleotides are known, including but not limitedto solid-phase synthesis which like peptide synthesis, has been fullyautomated in commercially available DNA synthesizers (See e.g., Itakuraet al. U.S. Pat. No. 4,598,049; Caruthers et al. U.S. Pat. No.4,458,066; and Itakura U.S. Pat. Nos. 4,401,796 and 4,373,071).

[0107] The nucleic acid molecules of the invention can be engineeredusing methods generally known in the art in order to alter PHI Proteinencoding sequences for reasons including alterations that modifycloning, processing, or expression of a PHI Protein. The molecules maybe engineered using DNA shuffling by random fragmentation and PCRreassembly of gene fragments and synthetic oligonucleotides.Site-directed mutagenesis may be used to introduce mutations, and insertnew restriction sites, alter glycosylation patterns, change codonpreference, produce splice variants, and the like.

[0108] Determination of whether a particular nucleic acid moleculeencodes a PHI Protein, can be accomplished by expressing the cDNA in anappropriate host cell by standard techniques, and testing the expressedprotein in the methods described herein. A cDNA encoding a PHI Protein,can be sequenced by standard techniques, such as dideoxynucleotide chaintermination or Maxam-Gilbert chemical sequencing, to determine thenucleic acid sequence and the predicted amino acid sequence of theencoded protein.

[0109] The initiation codon and untranslated sequences of a nucleic acidmolecule of the invention may be determined using computer softwaredesigned for the purpose, such as PC/Gene (IntelliGenetics Inc.,Calif.). The intron-exon structure and the transcription regulatorysequences of a nucleic acid molecule of the invention may be identifiedby using a nucleic acid molecule of the invention to probe a genomic DNAclone library. (See SEQ. ID. NO. 69 showing the intron/exon structure ofhuman PHIP and NDRP.) Regulatory elements can be identified usingstandard techniques. The function of the elements can be confirmed byusing these elements to express a reporter gene such as the lacZ genethat is operatively linked to the elements. These constructs may beintroduced into cultured cells using conventional procedures or intonon-human transgenic animal models. In addition to identifyingregulatory elements in DNA, such constructs may also be used to identifynuclear polypeptides interacting with the elements, using techniquesknown in the art.

[0110] The invention contemplates nucleic acid molecules comprising aregulatory sequence of a phip gene contained in appropriate vectors. Thevectors may contain sequences encoding heterologous polypeptides.“Heterologous polypeptide” refers to a polypeptide not naturally locatedin the cell, i.e. it is foreign to the cell.

[0111] In accordance with another aspect of the invention, the nucleicacid molecules isolated using the methods described herein are mutantphip gene alleles. For example, the mutant alleles may be isolated fromindividuals either known or proposed to have a genotype that contributesto symptoms of a particular condition or disease (e.g. a disorderassociated with insulin response, or cancer). Mutant alleles and mutantallele products may be used in therapeutic and diagnostic methodsdescribed herein. For example, a cDNA of a mutant phip gene may beisolated using PCR as described herein, and the DNA sequence of themutant allele may be compared to the normal allele to ascertain themutation(s) responsible for the loss or alteration of function of themutant gene product A genomic library can also be constructed using DNAfrom an individual suspected of or known to carry a mutant allele, or acDNA library can be constructed using RNA from tissue known, orsuspected to express the mutant allele. A nucleic acid encoding a normalphip gene or any suitable fragment thereof, may then be labeled and usedas a probe to identify the corresponding mutant allele in suchlibraries. Clones containing mutant sequences can be purified andsubjected to sequence analysis. In addition, an expression library canbe constructed using cDNA from RNA isolated from a tissue of anindividual known or suspected to express a mutant phip allele. Geneproducts from putatively mutant tissue may be expressed and screened,for example using antibodies specific for a PHI Protein as describedherein. Library clones identified using the antibodies can be purifiedand subjected to sequence analysis.

[0112] Nucleic acid molecules of the invention also includeoligonucleotides and fragments thereof, complementary to strategic sitesalong a sense PHIP nucleic acid molecule, e.g. antisenseoligonucleotides. Antisense oligonucleotides may be two to two hundrednucleotide bases long; more preferably ten to one hundred bases long,most preferably ten to forty bases long. Oligonucleotides are selectedfrom complementary or substantially complementary oligonucleotides tostrategic sites along a nucleic acid molecule of the invention (e.g.mRNA sense strand) that inhibit formation of a functional PHI Protein.Any combination or subcombination of antisense nucleic acid moleculesthat modulate a PHI Protein is suitable for use in the invention. Theantisense oligonucleotides may also include nucleotides flanking thecomplementary or substantially complementary to strategic sites or othersites along a PHIP nucleic acid molecule. The flanking portions arepreferably from about five to about fifty bases, preferably five toabout twenty bases in length. It is also preferable that the antisensemolecules be complementary to a non-conserved region of a PHIP nucleicacid molecule to minimize homology for nucleic acid molecules coding forother genes.

[0113] Sense and antisense oligonucleotides of the invention maycomprise oligonucleotides having modified sugar-phosphodiester backbones(or other sugar linkages, such as those described in WO91/06629). Suchsugar linkages may render the molecules resistant to endogenousnucleases. These oligonucleotides are relatively stable in vivo (i.e.capable of resisting enzymatic degradation) but retain their specificityfor binding to target nucleotide sequences. The oligonucleotides may becovalently linked to molecules that increase affinity of theoligonucleotides for a target nucleic acid sequence, such aspoly-(L-lysine). Intercalating agents, such as ellipticine, andalkylating agents or metal complexes may be linked to sense or antisenseoligonucleotides to modify the binding specificity for a targetsequence.

[0114] The invention also contemplates ribozymes, enzymatic RNAmolecules, that function to inhibit translation of a PHI Protein or oneor more molecules of a complex of the invention.

[0115] The antisense molecules and ribozymes contemplated within thescope of the invention may be prepared by any method known in the artfor the synthesis of nucleic acid molecules. For example, techniques forchemically synthesizing oligonucleotides such as solid phasephosphoramidite chemical synthesis may be used. RNA molecules may alsobe generated by in vitro and in vivo transcription of DNA sequencesencoding a PHI Protein. The DNA sequences may be incorporated intovectors with suitable RNA polymerase promoters including T7 or SP6. Inthe alternative, cDNA constructs that produce antisense RNAconstitutively or inducibly can be introduced into cell lines, cells, ortissues. The RNA molecules can be modified to increase intracellularstability and half-life, for example, by adding flanking sequences atthe 5′ and/or 3′ ends of the molecule, or using phosphorothioate or 2′O-methyl rather than phosphodiesterase linkages within the backbone ofthe molecule. The molecules can also be modified by insertingnontraditional bases such as inosine, queosine, and wybutosine, oracetyl-, methyl-, thio-, and similarly modified forms of adenine,cytidine, guanine, thymine, and uridine which are not as readilyrecognized by endogenous endonucleases.

[0116] 3. PHI Proteins

[0117] A PHI Protein is characterized by an N-terminal α-helical regionpredicting a coiled coil structure and a region containing twobromodomains. Amino acid sequences of PHI Protein comprise a sequence ofSEQ.ID.NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, 17, 71, 73, 75 or 77. “Aminoacid sequences” refer to an oligopeptide, peptide, polypeptide orprotein sequence and to naturally occurring or synthetic molecules.

[0118] In an embodiment of the invention an isolated PHI Protein isprovided that is encoded by a nucleic acid molecule selected from:

[0119] (a) a nucleic acid molecule comprising SEQ ID NO. 1, 4, 7, 9, 11,14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,or 34; and

[0120] (b) a nucleic acid molecule encoding a protein comprising SEQ IDNO: 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17;

[0121] wherein the protein is capable of forming a stable interactionwith a PH domain of insulin receptor substrate-1.

[0122] In preferred embodiments of the invention an isolated human PHIPis provided comprising SEQ ID NO. 2, 3, or 8, and a mouse PHIP isprovided comprising SEQ ID NO. 5, 6, or 10. The PHIP of SEQ ID NOs. 8and 10 are long forms of PHIP comprising a fusion of PHIP and neuronaldifferentiation-related protein (NDRP). The only difference with SEQ IDNOs. 2, 3, 5, and 6 is the N-terminal end which is encoded by differentexons. The sequence diverges at amino acid position 4 of the short forms(SEQ.ID.NOs. 2 and 5) in both human and mouse sequences. The long formof PHIP contains N-terminal alternatively spliced sequences.

[0123] A second member of the PHI Protein family, neuronaldifferentiation-related protein (NDRP), was identified which ispredominantly expressed in developing neurons and may be involved inneuronal regeneration and differentiation. The pre-carboxy terminalregion of NDRP is identical to the amino-terminal region of PHIP(residues 5-80). (See FIGS. 6 and 7). This region may correspond to aconserved functional domain in NDRP. FIGS. 7 and 8 show alignments ofthe amino acid sequences and nucleic acid sequences of human and mouseNDRP, respectively. SEQ. ID. NO. 69 shows the introns and exons of PHIPand NDRP. The sequence shown is the complementary sequence. The intronsare shown in black; PHIP exons are shown in blue; NDRP exons are shownin red; and PHIP/NDRP shared exons are shown in pink.

[0124] Therefore, the invention also relates to an isolated nucleic acidmolecule comprises:

[0125] (vi) a nucleic acid sequence having substantial sequence identityor sequence similarity with a nucleic acid sequence of one of SEQ. ID.NO. 35, and 39 through 63;

[0126] (vii) nucleic acid sequences comprising the sequence of one ofSEQ. ID. NO. 35, and 39 through 63, wherein T can also be U;

[0127] (viii) nucleic acid sequences complementary to (i), preferablycomplementary to the full nucleic acid sequence of one of SEQ. ID. NO.35, and 39through 63;

[0128] (ix) nucleic acid sequences differing from any of the nucleicacid sequences of (i), (ii), or (iii) in codon sequences due to thedegeneracy of the genetic code; or

[0129] (x) a fragment, or allelic or species variation of (i), (ii) or(iii).

[0130] An isolated neuronal differentiation-related protein is alsoprovided that is encoded by:

[0131] (a) a nucleic acid molecule comprising one of SEQ ID NO. 35, and39 through 63; or

[0132] (b) a nucleic acid molecule encoding a protein comprising SEQ IDNO: 36.

[0133] In preferred embodiments of the invention an isolated human NDRPis provided comprising SEQ ID NO. 36. The invention also includestruncations, analogs, proteins with substantial sequence identity,isoforms and mimetics of the NDRPs disclosed herein.

[0134] An ortholog of PHIP has also been identified which is referred toas “WDR9”. The full amino acid sequence for WDR9 is GenBank AccessionNo. Q9NSI6, and the nucleic acid sequence for WDR9 is spliced from thenucleic acid sequence of GenBank Accession No. AL163279. Partial aminoacid sequences for WDR9 are shown in SEQ ID NO. 64 and NO. 65. Aminoacid and nucleic acid sequence alignments of WD-Repeat Protein 9 andPHIP are shown in FIGS. 13, and 14, respectively.

[0135] In addition to proteins comprising an amino acid sequence ofSEQ.ID.NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17, the PHI Proteins of thepresent invention include truncations of a PHI Protein, analogs of a PHIProtein, and proteins having sequence identity or similarity to a PHIProtein, and truncations thereof as described herein. Truncated proteinsmay comprise, for example, peptides of between 3 and 275 amino acidresidues, ranging in size from a tripeptide to a 275 mer protein. In oneaspect of the invention, fragments of a PHI Protein are provided havingan amino acid sequence of at least five consecutive amino acids ofSEQ.ID. NO.2, 3, 5, 6, 8, 10, 12, 13, 15, or 17 where no amino acidsequence of five or more, six or more, seven or more, or eight or more,consecutive amino acids present in the fragment is present in apolypeptide other than a PHI Protein. In an embodiment of the inventionthe fragment is a stretch of amino acid residues of at least 12 to 20contiguous amino acids from particular sequences such as the sequencesof SEQ.ID. NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17. The fragments maybeimmunogenic and preferably are not immunoreactive with antibodies thatare immunoreactive to polypeptides other than a PHI Protein. In anembodiment, the fragments comprise an amino acid sequence of a bindingregion of a PHI Protein, for example a PH domain binding region (e.g.SEQ ID NO 12 or 13), or an IR binding region (e.g. SEQ ID NO. 15 or 17).(Also see description of peptides herein.)

[0136] The proteins of the invention may also include analogs of a PHIProtein, and/or truncations thereof as described herein, which mayinclude, but are not limited to a PHIP Protein, containing one or moreamino acid substitutions, insertions, and/or deletions. Amino acidsubstitutions may be of a conserved or non-conserved nature. Conservedamino acid substitutions involve replacing one or more amino acids of aPHI Protein amino acid sequence with amino acids of similar charge,size, and/or hydrophobicity characteristics. When only conservedsubstitutions are made the resulting analog is preferably functionallyequivalent to a PHI Protein. Non-conserved substitutions involvereplacing one or more amino acids of a PHI Protein amino acid sequencewith one or more amino acids which possess dissimilar charge, size,and/or hydrophobicity characteristics.

[0137] One or more amino acid insertions may be introduced into a PHIProtein. Amino acid insertions may consist of single amino acid residuesor sequential amino acids ranging from 2 to 15 amino acids in length.

[0138] Deletions may consist of the removal of one or more amino acids,or discrete portions from a PHI Protein sequence. The deleted aminoacids may or may not be contiguous. The lower limit length of theresulting analog with a deletion mutation is about 10 amino acids,preferably 20 to 40 amino acids. (Deletion mutants are described inExample 2 and in SEQ ID NOs. 67 and 68.)

[0139] An allelic variant at the polypeptide level differs from anotherpolypeptide by only one, or at most, a few amino acid substitutions. Aspecies variation of a PHI Protein of the invention is a variation whichis naturally occurring among different species of an organism.

[0140] The proteins of the invention include proteins with sequenceidentity or similarity to a PHI Protein and/or truncations thereof asdescribed herein. Such PHI Proteins may include proteins whose aminoacid sequences are comprised of the amino acid sequences of PHIP Proteinregions from other species that hybridize under selected hybridizationconditions (see discussion of stringent hybridization conditions herein)with a probe used to obtain a PHI Protein. These proteins will generallyhave the same regions which are characteristic of a PHI Protein.Preferably a protein will have substantial sequence identity forexample, about 65%, 70%, 75%, 80%, or 85% identity, preferably 90%identity, more preferably at least 95%, 96%, 97%, 98%, or 99% identity,and most preferably 98% identity with an amino acid sequence ofSEQ.ID.NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17. A percent amino acidsequence homology, similarity or identity is calculated as thepercentage of aligned amino acids that match the reference sequenceusing known methods as described herein. For example, a percent aminoacid sequence homology or identity is calculated as the percentage ofaligned amino acids that match the reference sequence, where thesequence alignment has been determined using the alignment algorithm ofDayhoff et al; Methods in Enzymology 91: 524-545 (1983).

[0141] The invention also contemplates isoforms of the proteins of theinvention. An isoform contains the same number and kinds of amino acidsas a protein of the invention, but the isoform has a different molecularstructure. Isoforms contemplated by the present invention preferablyhave the same properties as a protein of the invention as describedherein.

[0142] Still further the invention contemplates activated PHI Proteins.For example, a PHI Protein may be tyrosine phosphorylated orserine/threonine phosphorylated.

[0143] The invention provides molecules derived from a PHI Protein orbinding region thereof. The molecules are preferably peptides derivedfrom a PH domain binding region, an IR binding region, or a STAT bindingregion. In embodiments of the invention the peptides consist essentiallyof SEQ ID. NO. 12, 13, 15, or 17. Peptides may also be derived from abinding region of a PH domain containing protein, receptor thatinteracts with a protein of the IRS protein family, or STATtranscription factor, that interact with or bind directly or indirectlywith a PHI Protein binding region.

[0144] All of these peptides, as well as molecules substantiallyhomologous, complementary or otherwise functionally or structurallyequivalent to these peptides may be used for purposes of the presentinvention. In addition to a full-length binding region (e.g. PH domainbinding region, an IR binding region, or a STAT binding region),truncations of the peptides are contemplated. Truncated peptides maycomprise peptides of about 5 to 200 amino acid residues, preferably 5 to100 amino acid residues, more preferably 5 to 50 amino acid residues.

[0145] The invention also relates to novel chimeric proteins comprisingat least one PHI Protein or peptide of the invention fused to, orintegrated into, a target protein, and/or a targeting domain capable ofdirecting the chimeric protein to a desired cellular component or celltype or tissue. The chimeric proteins may also contain additional aminoacid sequences or domains. The chimeric proteins are recombinant in thesense that the various components are from different sources, and assuch are not found together in nature (i.e. are heterologous). A targetprotein is a protein that is selected for insertion of a PH domainbinding region, IR binding region, or STAT binding region, and forexample may be a protein that is mutated or over expressed in a diseasecondition. The targeting domain can be a membrane spanning domain, amembrane binding domain, or a sequence directing the protein toassociate with for example vesicles or with the nucleus. The targetingdomain can target the chimeric protein to a particular cell type ortissue. For example, the targeting domain can be a cell surface ligandor an antibody against cell surface antigens of a target tissue (e.g.tumor antigens).

[0146] Cyclic derivatives of peptides or chimeric proteins of theinvention are also part of the present invention. Cyclization may allowthe peptide or chimeric protein to assume a more favorable conformationfor association with other molecules. Cyclization may be achieved usingtechniques known in the art. For example, disulfide bonds may be formedbetween two appropriately spaced components having free sulfhydrylgroups, or an amide bond may be formed between an amino group of onecomponent and a carboxyl group of another component. Cyclization mayalso be achieved using an azobenzene-containing amino acid as describedby Ulysse, L., et al., J. Am. Chem. Soc. 1995, 117, 8466-8467. Thecomponents that form the bonds may be side chains of amino acids,non-amino acid components or a combination of the two.

[0147] It may be desirable to produce a cyclic peptide which is moreflexible than the cyclic peptides containing peptide bond linkages asdescribed above. A more flexible peptide may be prepared by introducingcysteines at the right and left position of the peptide and forming adisulphide bridge between the two cysteines. The relative flexibility ofa cyclic peptide can be determined by molecular dynamics simulations.

[0148] Combined with certain formulations, peptides can be effectiveintracellular agents. However, in order to increase the efficacy ofpeptides, a fusion peptide can be prepared comprising a second peptidewhich promotes “transcytosis”, e.g. uptake of the peptide by epithelialcells. To illustrate, a peptide of the invention can be provided as partof a fusion polypeptide with all or a fragment of the N-terminal domainof the HIV protein Tat, e.g. residues 1-72 of Tat or a smaller fragmentthereof which can promote transcytosis. In other embodiments, a peptideof the invention can be provided as a fusion polypeptide with all or aportion of an antennapedia protein. To further illustrate, a peptide ofthe invention can be provided as a chimeric peptide which includes aheterologous peptide sequence (“internalizing peptide”) which drives thetranslocation of an extracellular form of a peptide sequence across acell membrane in order to facilitate intracellular localization of thepeptide.

[0149] Hydrophilic polypeptides may be also be physiologicallytransported across the membrane barriers by coupling or conjugating thepolypeptide to a transportable peptide which is capable of crossing themembrane by receptor-mediated transcytosis. Examples of internalizingpeptides of this type can be generated using all or a portion of, e.g. ahistone, insulin, transferrin, basic albumin, prolactin and insulin-likegrowth factor I (IGF-I), insulin-like growth factor II (IGF-II) or othergrowth factors.

[0150] Another class of translocating/internalizing peptides exhibitspH-dependent membrane binding. An example of a pH-dependentmembrane-binding internalizing peptide in this regard isaa1-aa2-aa3-EAALA(EALA)4-EALEALAA-amide, which represents a modificationof the peptide sequence of Subbarao et al. (Biochemistry 26:2964, 1987).

[0151] Internalizing peptides include peptides of apo-lipoprotein A-1and B; peptide toxins, such as melittin, bombolittin, delta hemolysinand the pardaxins; antibiotic peptides, such as alamethicin; peptidehormones, such as calcitonin, corticotrophin releasing factor, betaendorphin, glucagon, parathyroid hormone, pancreatic polypeptide; andpeptides corresponding to signal sequences of numerous secretedproteins. In addition, internalizing peptides may be modified throughattachment of substituents that enhance the alpha-helical character ofthe internalizing peptide at acidic pH.

[0152] Other suitable internalizing peptides within the presentinvention include hydrophobic domains that are “hidden” at physiologicalpH, but are exposed in the low pH environment of the target cellendosome. Such internalizing peptides may be modeled after sequencesidentified in, e.g., Pseudomonas exotoxin A, clathrin, or Diphtheriatoxin.

[0153] Pore-forming proteins or peptides may also serve as internalizingpeptides. Pore-forming proteins or peptides may be obtained or derivedfrom, for example, C9 complement protein, cytolytic T-cell molecules orNK-cell molecules.

[0154] Membrane intercalation of an internalizing peptide may besufficient for translocation of the CPD peptide or peptidomimetic,across cell membranes. However, translocation may be improved by fusingto the internalizing peptide a substrate for intracellular enzymes(i.e., an “accessory peptide”). Suitable accessory peptides includepeptides that are kinase substrates, peptides that possess a singlepositive charge, and peptides that contain sequences which areglycosylated by membrane-bound glycotransferases.

[0155] An accessory peptide can be used to enhance interaction of apeptide or peptide mimetic of the invention with a target cell. Examplesof suitable accessory peptides for this use include peptides derivedfrom cell adhesion proteins containing the sequence “RGD”, or peptidesderived from laminin containing the sequence CDPGYIGSRC.

[0156] An internalizing and accessory peptide can each, independently,be added to a peptide or peptide mimetic of the present invention byeither chemical cross-linking or in the form of a fusion protein. Forfusion proteins, unstructured polypeptide linkers may be includedbetween each of the peptide moieties.

[0157] An internalization peptide will generally be sufficient to alsodirect export of the polypeptide. However, when certain accessorypeptides are used, such as an RGD sequence, it may be necessary toinclude a secretion signal sequence to direct export of the fusionprotein from its host cell. A secretion signal sequence may be locatedat the extreme N-terminus, and is (optionally) flanked by a proteolyticsite between the secretion signal and the rest of the fusion protein. Incertain instances, it may also be desirable to include a nuclearlocalization signal as part of a peptide of the invention.

[0158] In the generation of fusion polypeptides including a peptide ofthe invention, it may be necessary to include unstructured linkers inorder to ensure proper folding of the various peptide domains. Manysynthetic and natural linkers are known in the art and can be adaptedfor use in the present invention, for example the (Gly₃Ser)₄ linker.

[0159] Peptide mimetics may be designed based on information obtained bysystematic replacement of L-amino acids by D-amino acids, replacement ofside chains with groups having different electronic properties, and bysystematic replacement of peptide bonds with amide bond replacements.Local conformational constraints can also be introduced to determineconformational requirements for activity of a candidate peptide mimetic.The mimetics may include isosteric amide bonds, or D-amino acids tostabilize or promote reverse turn conformations and to help stabilizethe molecule. Cyclic amino acid analogues may be used to constrain aminoacid residues to particular conformational states. The mimetics can alsoinclude mimics of inhibitor peptide secondary structures. Thesestructures can model the 3-dimensional orientation of amino acidresidues into the known secondary conformations of proteins. Peptoidsmay also be used which are oligomers of N-substituted amino acids andcan be used as motifs for the generation of chemically diverse librariesof novel molecules.

[0160] Peptides of the invention may be developed using a biologicalexpression system. The use of such a system allows the production oflarge libraries of random peptide sequences and the screening of theselibraries for peptide sequences that bind to particular proteins.Libraries may be produced by cloning synthetic DNA that encodes randompeptide sequences into appropriate expression vectors. (see Christian etal 1992, J. Mol. Biol. 227:711; Devlin et al, 1990 Science 249:404;Cwirla et al 1990, Proc. Natl. Acad, Sci. USA, 87:6378). Libraries mayalso be constructed by concurrent synthesis of overlapping peptides (seeU.S. Pat. No. 4,708,871).

[0161] The invention contemplates peptide mimetics i.e. compounds basedon, or derived from, peptides and proteins. Peptide mimetics of thepresent invention typically can be obtained by structural modificationof a known PHI Protein sequence using unnatural amino acids,conformational restraints, isosteric replacement, and the like. Thepeptide mimetics constitute the continum of structural space betweenpeptides and non-peptide synthetic structures; peptide mimetics of theinvention may be useful, therefore, in delineating pharmacophores and inhelping to translate peptides into nonpeptide compounds with theactivity of the parent PHI peptides.

[0162] Moreover, mimetopes of peptides of the invention can be provided.Such peptide mimetics can have such attributes as being non-hydrolyzable(e.g., increased stability against proteases or other physiologicalconditions which degrade the corresponding peptide), increasedspecificity and/or potency, and increased cell permeability forintracellular localization of the peptidomimetic. Peptide analogs of thepresent invention can be generated using, for example, benzodiazepines(e.g., see Freidinger et al. in Peptides: Chemistry and Biology, G. R.Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), substitutedgama lactam rings (Garvey et al. in Peptides: Chemistry and Biology, G.R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988, p123), C-7mimics (Huffman et al. in Peptides: Chemistry and Biology, G. R.Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988, p. 105),keto-methylene pseudopeptides (Ewenson et al. (1986) J Med Chem 29:295;and Ewenson et al. in Peptides: Structure and Function (Proceedings ofthe 9th American Peptide Symposium) Pierce Chemical Co. Rockland, Ill.,1985), β-turn dipeptide cores (Nagai et al. (1985) Tetrahedron Lett26:647; and Sato et al. (1986) J Chem Soc Perkin Trans 1:1231),α-aminoalcohols (Gordon et al. (1985) Biochem Biophys Res Commun126:419;and Dann et al. (1986) Biochem Biophys Res Commun 134:71),diaminoketones (Natarajan et al. (1984) Biochem Biophys Res Commun124:141), and methyleneamino-modifed (Roark et al. in Peptides:Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden,Netherlands, 1988, p134). (See generally, Session III: Analytic andsynthetic methods, in in Peptides: Chemistry and Biology, G. R. Marshalled., ESCOM Publisher: Leiden, Netherlands, 1988)

[0163] In addition to a variety of sidechain replacements which can becarried out to generate peptide mimetics, the present inventionspecifically contemplates the use of conformationally restrained mimicsof peptide secondary structure. Many surrogates have been developed forthe amide bond of peptides. Exemplary surrogates for the amide bondinclude the following groups (i) trans-olefins, (ii) fluoroalkene, (iii)methyleneamino, (iv) phosphonamides, and (v) sulfonamides. Peptidemimietics can also be based on more substantial modifications of thebackbone of a PHI peptide. Peptide mimetics which are within thiscategory include (i) retro-inverso analogs, and (ii) N-alkyl glycineanalogs (so-called peptoids).

[0164] Combinatorial chemistry methods may also be brought to bear, c.f. Verdine et al. PCT publication WO9948897, on the development of newpeptide mimetics. For example, a so-called “peptide morphing” strategymay be used that focuses on the random generation of a library ofpeptide analogs that comprise a wide range of peptide bond substitutes.

[0165] Another class of peptide mimetic derivatives include phosphonatederivatives. The synthesis of such phosphonate derivatives can beadapted from methods known by skilled artisans. (See, for example, Lootset al. in Peptides: Chemistry and Biology, (Escom Science Publishers,Leiden, 1988, p. 118); Petrillo et al. in Peptides: Structure andFunction (Proceedings of the 9th American Peptide Symposium, PierceChemical Co. Rockland, Ill., 1985).

[0166] Many other peptide mimetic structures are known in the art andcan be readily adapted for use in the present invention. A peptidemimetic of the invention may incorporate a 1-azabicyclo[4.3.0]nonanesurrogate (see Kim et al. (1997) J. Org. Chem. 62:2847), an N-acylpiperazic acid (see Xi et al. (1998) J. Am. Chem. Soc. 120:80), or a2-substituted piperazine moiety as a constrained amino acid analogue(see Williams et al. (1996) J. Med. Chem. 39:1345-1348. Certain aminoacid residues may be replaced with aryl and bi-aryl moieties, e.g.,monocyclic or bicyclic aromatic or heteroaromatic nucleus, or abiaromatic, aromatic-heteroaromatic, or biheteroaromatic nucleus.

[0167] Peptide mimetics of the invention can be optimized by, e.g.,combinatorial synthesis techniques combined with high throughputscreening.

[0168] The present invention also includes PHI Proteins or peptides ofthe invention conjugated with a selected protein, or a marker protein(see below) to produce fusion proteins. Additionally, immunogenicportions of a PHI Protein or a peptide of the invention are within thescope of the invention.

[0169] A protein or peptide of the invention may be prepared usingrecombinant DNA methods. Accordingly, the nucleic acid molecules of thepresent invention having a sequence which encodes a protein or peptideof the invention may be incorporated in a known manner into anappropriate expression vector which ensures good expression of theprotein. Possible expression vectors include but are not limited tocosmids, plasmids, or modified viruses (e.g. replication defectiveretroviruses, adenoviruses and adeno-associated viruses), so long as thevector is compatible with the host cell used. Human artificialchromosomes (HACs) may be used to deliver larger fragments of DNA thatcan be contained and expressed in a plasmid.

[0170] The invention therefore contemplates a recombinant expressionvector of the invention containing a nucleic acid molecule of theinvention, and the necessary regulatory sequences for the transcriptionand translation of the inserted protein-sequence. Suitable regulatorysequences may be derived from a variety of sources, including bacterial,fungal, viral, mammalian, or insect genes [For example, see theregulatory sequences described in Goeddel, Gene Expression Technology:Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)].Selection of appropriate regulatory sequences is dependent on the hostcell chosen as discussed below, and may be readily accomplished by oneof ordinary skill in the art. The necessary regulatory sequences may besupplied by the native protein and/or its flanking regions.

[0171] The invention further provides a recombinant expression vectorcomprising a DNA nucleic acid molecule of the invention cloned into theexpression vector in an antisense orientation. That is, the DNA moleculeis linked to a regulatory sequence in a manner which allows forexpression, by transcription of the DNA molecule, of an RNA moleculewhich is antisense to the nucleic acid sequence of a protein of theinvention or a fragment thereof. Regulatory sequences linked to theantisense nucleic acid can be chosen which direct the continuousexpression of the antisense RNA molecule in a variety of cell types, forinstance a viral promoter and/or enhancer, or regulatory sequences canbe chosen which direct tissue or cell type specific expression ofantisense RNA.

[0172] The recombinant expression vectors of the invention may alsocontain a marker gene which facilitates the selection of host cellstransformed or transfected with a recombinant molecule of the invention.Examples of marker genes are genes encoding a protein such as G418 andhygromycin which confer resistance to certain drugs, β-galactosidase,chloramphenicol acetyltransferase, firefly luciferase, or animmunoglobulin or portion thereof such as the Fc portion of animmunoglobulin preferably IgG. The markers can be introduced on aseparate vector from the nucleic acid of interest.

[0173] The recombinant expression vectors may also contain genes thatencode a fusion moiety which provides increased expression of therecombinant protein; increased solubility of the recombinant protein;and aid in the purification of the target recombinant protein by actingas a ligand in affinity purification. For example, a proteolyticcleavage site may be added to the target recombinantproteinto allowseparation of the recombinant protein from the fusion moiety subsequentto purification of the fusion protein. Typical fusion expression vectorsinclude pET (Novagen) that have a histadine tag, pGEX (Amrad Corp.,Melbourne, Australia), pMAL (New England Biolabs, Beverly, Mass.) andpRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase(GST), maltose E binding protein, or protein A, respectively, to therecombinant protein.

[0174] The recombinant expression vectors may be introduced into hostcells to produce a transformant host cell. “Transformant host cells”include host cells which have been transformed or transfected with arecombinant expression vector of the invention. The terms “transformedwith”, “transfected with”, “transformation” and “transfection” encompassthe introduction of a nucleic acid (e.g. a vector) into a cell by one ofmany standard techniques. Prokaryotic cells can be transformed with anucleic acid by, for example, electroporation or calcium-chloridemediated transformation. A nucleic acid can be introduced into mammaliancells via conventional techniques such as calcium phosphate or calciumchloride co-precipitation, DEAE-dextran-mediated transfection,lipofectin, electroporation or microinjection. Suitable methods fortransforming and transfecting host cells can be found in Sambrook et al.(Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring HarborLaboratory press (1989)), and other laboratory textbooks.

[0175] Suitable host cells include a wide variety of prokaryotic andeukaryotic host cells. For example, the proteins of the invention may beexpressed in bacterial cells such as E. coli, insect cells (usingbaculovirus), yeast cells, or mammalian cells. Other suitable host cellscan be found in Goeddel, Gene Expression Technology: Methods inEnzymology 185, Academic Press, San Diego, Calif. (1991).

[0176] A host cell may also be chosen which modulates the expression ofan inserted nucleic acid sequence, or modifies (e.g. glycosylation orphosphorylation) and processes (e.g. cleaves) the protein in a desiredfashion. Host systems or cell lines may be selected which have specificand characteristic mechanisms for post-translational processing andmodification of proteins. For example, eukaryotic host cells includingCHO, VERO, BHK, HeLA, COS, MDCK, 293, 3T3, and W138 may be used. Forlong-term high-yield stable expression of the protein, cell lines andhost systems which stably express the gene product may be engineered.

[0177] Host cells and in particular cell lines produced using themethods described herein may be particularly useful in screening andevaluating compounds that modulate the activity of a PHI Protein.

[0178] A PHI Protein may be expressed in non-human transgenic animalsincluding but not limited to mice, rats, rabbits, guinea pigs,micro-pigs, goats, sheep, pigs, non-human primates (e.g. baboons,monkeys, and chimpanzees) [see Hammer et al. (Nature 315:680-683, 1985),Palmiter et al. (Science 222:809-814, 1983), Brinster et al. (Proc Natl.Acad. Sci USA 82:44384442, 1985), Palmiter and Brinster (Cell.41:343-345, 1985) and U.S. Pat. No. 4,736,866)]. Procedures known in theart may be used to introduce a nucleic acid molecule of the inventionencoding a PHI Protein into animals to produce the founder lines oftransgenic animals. Such procedures include pronuclear microinjection,retrovirus mediated gene transfer into germ lines, gene targeting inembryonic stem cells, electroporation of embryos, and sperm-mediatedgene transfer.

[0179] The present invention contemplates a transgenic animal thatcarries the phip gene in all their cells, and animals which carry thetransgene in some but not all their cells. The transgene may beintegrated as a single transgene or in concatamers. The transgene may beselectively introduced into and activated in specific cell types (Seefor example, Lasko et al, 1992 Proc. Natl. Acad. Sci. USA 89: 6236). Thetransgene may be integrated into the chromosomal site of the endogenousgene by gene targeting. The transgene may be selectively introduced intoa particular cell type inactivating the endogenous gene in that celltype (See Gu et al Science 265: 103-106).

[0180] The expression of a recombinant PHI Protein in a transgenicanimal may be assayed using standard techniques. Initial screening maybe conducted by Southern Blot analysis, or PCR methods to analyzewhether the transgene has been integrated. The level of mRNA expressionin the tissues of transgenic animals may also be assessed usingtechniques including Northern blot analysis of tissue samples, in situhybridization, and RT-PCR. Tissue may also be evaluated immunocy tochemically using antibodies against a PHI Protein.

[0181] Proteins or peptides of the invention may also be prepared bychemical synthesis using techniques well known in the chemistry ofproteins such as solid phase synthesis (Merrifield, 1964, J. Am. Chem.Assoc. 85:2149-2154) or synthesis in homogenous solution (Houbenweyl,1987, Methods of Organic Chemistry, ed. E. Wansch, Vol. 15 I and II,Thieme, Stuttgart).

[0182] N-terminal or C-terminal fusion proteins comprising a protein orpeptide of the invention conjugated with other molecules, such asproteins, may be prepared by fusing, through recombinant techniques, theN-terminal or C-terminal of a protein or peptide, and the sequence of aselected protein or marker protein with a desired biological function.The resultant fusion proteins contain the protein or peptide fused tothe selected protein or marker protein as described herein. Examples ofproteins which may be used to prepare fusion proteins includeimmunoglobulins, glutathione-S-transferase (GST), hemagglutinin (HA),and truncated myc.

[0183] 4. Complexes of the Invention

[0184] A complex of the invention comprises a PHI protein or a bindingregion thereof, and a binding partner. A binding partner includes a PHdomain containing protein, a receptor that interacts with a protein ofthe IRS protein family, and a STAT transcription factor, or a bindingregion thereof, that interacts with a PHI Protein or binding regionthereof. In aspects of the invention complexes are provided comprising(a) a PHI Protein or a PH domain binding region, and a PH domaincontaining protein or a PH domain; (b) a PHI Protein or an IR bindingregion, and a receptor that interacts with a protein of the IRS proteinfamily, or a binding region thereof; or, (c) a PHI Protein or a STATbinding region, and a STAT transcription factor or a binding regionthereof that interacts with a PHI Protein. It will be appreciated thatthe complexes may comprise only the regions of the interacting moleculesand such other flanking sequences as are necessary to maintain theactivity of the complexes. Under physiological conditions theinteracting molecules in a complex are capable of forming a stable,non-covalent interaction with the other molecules in the complex.

[0185] 5. Antibodies

[0186] A PHI Protein, peptide, or complex of the invention can be usedto prepare antibodies specific for the protein, peptide or complex. Theinvention can employ intact monoclonal or polyclonal antibodies, andimmunologically active fragments (e.g. a Fab, (Fab)₂ fragment, or Fabexpression library fragments and epitope-binding fragments thereof), anantibody heavy chain, and antibody light chain, humanized antibodies, agenetically engineered single chain Fv molecule (Ladner et al, U.S. Pat.No. 4,946,778), or a chimeric antibody, for example, an antibody whichcontains the binding specificity of a murine antibody, but in which theremaining portions are of human origin. Antibodies including monoclonaland polyclonal antibodies, fragments and chimeras, may be prepared usingmethods known to those skilled in the art.

[0187] Antibodies can be prepared which recognize a distinct epitope inan unconserved region of a PHI Protein. An unconserved region of theprotein is one that does not have substantial sequence homology to otherproteins. A region from a conserved region such as a well-characterizeddomain can also be used to prepare an antibody to a conserved region ofa PHI Protein. Antibodies having specificity for a PHI Protein may alsobe raised from fusion proteins created by expressing fusion proteins inbacteria as described herein. In an embodiment, antibodies are preparedwhich are specific for a binding region of a PH Protein or a molecule ina complex of the invention.

[0188] Antibodies may be produced that are capable of specificallyrecognizing a complex or an epitope thereof, or of specificallyrecognizing an epitope on either of the interacting molecules of thecomplex, in particular epitopes that would not be recognized by theantibody when the molecules are present separate and apart from thecomplex. The antibodies may be capable of interfering with the formationof a complex of the invention and as described below they may beadministered for the treatment of disorders involving a molecule capableof forming the complex with an interacting molecule (e.g. PHI Protein orbinding region thereof, a PH domain, or PH domain containing protein).

[0189] Antibodies specific for a PHI Protein or complex of the inventionmay be used to detect PHI Protein or the complexes in tissues and todetermine their tissue distribution. In vitro and in situ detectionmethods using the antibodies of the invention may be used to assist inthe prognostic and/or diagnostic evaluation of conditions or diseasesinvolving a PHI Protein, a complex of the invention, or a signaltransduction pathway, including but not limited to proliferative and/ordifferentiative disorders associated with a PHI Protein or complex ofthe invention. Some genetic diseases may include mutations at thebinding domain regions of the interacting molecules in the complexes ofthe invention. Therefore, if a complex of the invention is implicated ina genetic disorder, it may be possible to use PCR to amplify DNA fromthe binding regions to quickly check if a mutation is contained withinone of the domains. Primers can be made corresponding to the flankingregions of the domains and standard sequencing methods can be employedto determine whether a mutation is present. This method does not requireprior chromosome mapping of the affected gene and can save time byobviating sequencing the entire gene encoding a defective protein.

[0190] 6. Applications

[0191] The nucleic acid molecules, PHI Proteins, antibodies, peptides,complexes compounds, substances and agents of the invention may be usedin the prognostic and diagnostic evaluation of conditions and diseasesmediated by a PHI Protein, a complex of the invention or an individualcomponent thereof, or a signal transduction pathway, (e.g. cancer ordisorders associated with insulin response), and the identification ofsubjects with a predisposition to such conditions or diseases (Section6.1.1 and 6.1.2 below). Methods for detecting nucleic acid molecules andPHI Proteins of the invention, can be used to monitor diseases andconditions by detecting PHI Proteins and nucleic acid molecules encodingPHI Proteins. It would also be apparent to one skilled in the art thatthe methods described herein may be used to study the developmentalexpression of PHI Proteins and, accordingly, will provide furtherinsight into the role of PHI Proteins. The applications of the presentinvention also include methods for the identification of compounds thatmodulate the biological activity of nucleic acid molecules encodingPHIP, PHI Proteins, peptides, complexes of the invention or componentsthereof, or mediate signal transduction pathways (e.g. IGF-R signalingpathways) (Section 6.2). The compounds, antibodies etc. may be used forthe treatment of diseases and conditions mediated by a PHI Protein, acomplex of the invention, or a signal transduction pathway (e.g. canceror disorders associated with insulin response) (Section 6.3).

[0192] 6.1 Diagnostic Methods

[0193] A variety of methods can be employed for the diagnostic andprognostic evaluation of diseases and conditions mediated by a PHIProtein, a complex of the invention or an individual component thereof,or a signal transduction pathway (e.g. cancer or disorders associatedwith insulin response), and the identification of subjects with apredisposition to such diseases and conditions. Such methods may, forexample, utilize nucleic acid molecules of the invention, and fragmentsthereof, and antibodies directed against PHI Proteins, including peptidefragments, or complexes of the invention. In particular, the nucleicacids and antibodies may be used, for example, for (1) the detection ofthe presence of PHIP mutations, or the detection of either over- orunder-expression of PHIP mRNA relative to anon-disorder state or thequalitative or quantitative detection of alternatively spliced forms ofPHIP transcripts which may correlate with certain conditions orsusceptibility toward such conditions; and (2) the detection of eitheran over- or an under-abundance of PHI Proteins relative to anon-disorder state or the presence of a modified (e.g., less than fulllength) PHI Protein which correlates with a disorder state, or aprogression toward a disorder state.

[0194] The methods described herein may be performed by utilizingpre-packaged diagnostic kits comprising at least one nucleic acidmolecule or antibody described herein, which may be conveniently used,e.g., in clinical settings, to screen and diagnose patients and toscreen and identify those individuals exhibiting a predisposition todeveloping a disorder.

[0195] Nucleic acid-based detection techniques are described, below, inSection 6.1.1. Peptide detection techniques are described, below, inSection 6.1.2. The samples that may be analyzed using the methods of theinvention include those which are known or suspected to express phip orcontain PHI Proteins. The samples may be derived from a patient or acell culture, and include but are not limited to biological fluids,tissue extracts, freshly harvested cells, and lysates of cells whichhave been incubated in cell cultures.

[0196] Oligonucleotides or longer fragments derived from any of thenucleic acid molecules of the invention may be used as targets in amicroarray. The microarray can be used to simultaneously monitor theexpression levels of large numbers of genes and to identify geneticvariants, mutations, and polymorphisms. The information from themicroarray may be used to determine gene function, to understand thegenetic basis of a disorder, to diagnose a disorder, and to develop andmonitor the activities of therapeutic agents.

[0197] The preparation, use, and analysis of microarrays are well knownto a person skilled in the art. (See, for example, Brennan, T. M. et al.(1995) U.S. Pat. No. 5,474,796; Schena, et al. (1996) Proc. Natl. Acad.Sci. 93:10614-10619; Baldeschweiler et al. (1995), PCT ApplicationWO95/251116; Shalon, D. et al. (I 995) PCT application WO95/35505,Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. 94:2150-2155; andHeller, M. J. et al. (1997) U.S. Pat. No. 5,605,662.)

[0198] 6.1.1 Methods for Detecting Nucleic Acid Molecules of theInvention

[0199] The nucleic acid molecules of the invention allow those skilledin the art to construct nucleotide probes for use in the detection ofnucleic acid sequences of the invention in samples. Suitable probesinclude nucleic acid molecules based on nucleic acid sequences encodingat least 5 sequential amino acids from regions of the PHI Protein,preferably they comprise 15 to 30 nucleotides. A nucleotide probe may belabeled with a detectable substance such as a radioactive label whichprovides for an adequate signal and has sufficient half-life such as³²P, ³H, ¹⁴C or the like. Other detectable substances which may be usedinclude antigens that are recognized by a specific labeled antibody,fluorescent compounds, enzymes, antibodies specific for a labeledantigen, and luminescent compounds. An appropriate label may be selectedhaving regard to the rate of hybridization and binding of the probe tothe nucleotide to be detected and the amount of nucleotide available forhybridization. Labeled probes may be hybridized to nucleic acids onsolid supports such as nitrocellulose filters or nylon membranes asgenerally described in Sambrook et al, 1989, Molecular Cloning, ALaboratory Manual (2nd ed.). The nucleic acidprobes may be used todetect genes, preferably in human cells, that encode PHI Proteins. Thenucleotide probes may also be useful in the diagnosis of cancer, inmonitoring the progression of diseases and conditions mediated by a PHIProtein, a complex of the invention, or a signal transduction pathway(e.g. cancer or disorders associated with insulin response); ormonitoring a therapeutic treatment.

[0200] The probe may be used in hybridization techniques to detect genesthat encode PHI Proteins. The technique generally involves contactingand incubating nucleic acids (e.g. recombinant DNA molecules, clonedgenes) obtained from a sample from a patient or other cellular sourcewith a probe of the present invention under conditions favorable for thespecific annealing of the probes to complementary sequences in thenucleic acids. After incubation, the non-annealed nucleic acids areremoved, and the presence of nucleic acids that have hybridized to theprobe if any are detected.

[0201] The detection of nucleic acid molecules of the invention mayinvolve the amplification of specific gene sequences using anamplification method such as PCR, followed by the analysis of theamplified molecules using techniques known to those skilled in the art.Suitable primers can be routinely designed by one of skill in the art.

[0202] Genomic DNA may be used in hybridization or amplification assaysof biological samples to detect abnormalities involving phip structure,including point mutations, insertions, deletions, and chromosomalrearrangements. For example, direct sequencing, single strandedconformational polymorphism analyses, heteroduplex analysis, denaturinggradient gel electrophoresis, chemical mismatch cleavage, andoligonucleotide hybridization may be utilized.

[0203] Genotyping techniques known to one skilled in the art can be usedto type polymorphisms that are in close proximity to the mutations in aphip gene. The polymorphisms may be used to identify individuals infamilies that are likely to carry mutations. If a polymorphism exhibitslinkage disequalibrium with mutations in a phip gene, it can also beused to screen for individuals in the general population likely to carrymutations. Polymorphisms which may be used include restriction fragmentlength polymorphisms (RFLPs), single-base polymorphisms, and simplesequence repeat polymorphisms (SSLPs).

[0204] A probe of the invention may be used to directly identify RFLPs.A probe or primer of the invention can additionally be used to isolategenomic clones such as YACs, BACs, PACs, cosmids, phage or plasmids. TheDNA in the clones can be screened for SSLPs using hybridization orsequencing procedures.

[0205] Hybridization and amplification techniques described herein maybe used to assay qualitative and quantitative aspects of phipexpression. For example, RNA may be isolated from a cell type or tissueknown to express phip and tested utilizing the hybridization (e.g.standard Northern analyses) or PCR techniques referred to herein. Thetechniques may be used to detect differences in transcript size whichmay be due to normal or abnormal alternative splicing. The techniquesmay be used to detect quantitative differences between levels of fulllength and/or alternatively spliced transcripts detected in normalindividuals relative to those individuals exhibiting symptoms of adisease or condition (e.g. including cancer or a disorder associatedwith insulin response).

[0206] The primers and probes may be used in the above described methodsin situ i.e directly on tissue sections (fixed and/or frozen) of patienttissue obtained from biopsies or resections.

[0207] 6.1.2 Methods for Detecting PHI Proteins

[0208] Antibodies specifically reactive with a PHI Protein, orderivatives, such as enzyme conjugates or labeled derivatives, may beused to detect PHI Proteins in various samples (e.g. biologicalmaterials). They may be used as diagnostic or prognostic reagents andthey may be used to detect abnormalities in the level of PHI Proteinexpression, or abnormalities in the structure, and/or temporal, tissue,cellular, or subcellular location of a PHI Protein. Antibodies may alsobe used to screen potentially therapeutic compounds in vitro todetermine their effects on diseases and conditions mediated by a PHIProtein, a complex of the invention, or a signal transduction pathway(e.g. cancer or disorders associated with insulin response), and otherconditions. In vitro immunoassays may also be used to assess or monitorthe efficacy of particular therapies. The antibodies of the inventionmay also be used in vitro to determine the level of phip expression incells genetically engineered to produce a PHI Protein.

[0209] The antibodies may be used in any known immunoassays which relyon the binding interaction between an antigenic determinant of a PHIProtein and the antibodies. Examples of such assays areradioimmunoassays, enzyme immunoassays (e.g. ELISA), immunofluorescence,immunoprecipitation, latex agglutination, hemagglutination, andhistochemical tests. The antibodies may be used to detect and quantifyPHI Proteins in a sample in order to determine its role in particularcellular events or pathological states, and to diagnose and treat suchpathological states.

[0210] In particular, the antibodies of the invention may be used inimmuno-histochemical analyses, for example, at the cellular andsub-subcellular level, to detect a PH Protein, to localize it toparticular cells and tissues, and to specific subcellular locations, andto quantitate the level of expression.

[0211] Cytochemical techniques known in the art for localizing antigensusing light and electron microscopy may be used to detect a PHI Protein.Generally, an antibody of the invention may be labeled with a detectablesubstance and a PHI Protein may be localised in tissues and cells basedupon the presence of the detectable substance. Examples of detectablesubstances include, but are not limited to, the following: radioisotopes(e.g., ³ H, ¹⁴C., ³⁵S, ¹²⁵I, ¹³¹I, fluorescent labels (e.g., FITC,rhodamine, lanthanide phosphors), luminescent labels such as luminol;enzymatic labels (e.g., horseradish peroxidase, beta-galactosidase,luciferase, alkaline phosphatase, acetylcholinesterase), biotinyl groups(which can be detected by marked avidin e.g., streptavidin containing afluorescent marker or enzymatic activity that can be detected by opticalor calorimetric methods), predetermined protein epitopes recognized by asecondary reporter (e.g., leucine zipper pair sequences, binding sitesfor secondary antibodies, metal binding domains, epitope tags). In someembodiments, labels are attached via spacer arms of various lengths toreduce potential steric hindrance. Antibodies may also be coupled toelectron dense substances, such as ferritin or colloidal gold, which arereadily visualised by electron microscopy.

[0212] The antibody or sample may be immobilized on a carrier or solidsupport which is capable of immobilizing cells, antibodies etc. Forexample, the carrier or support may be nitrocellulose, or glass,polyacrylamides, gabbros, and magnetite. The support material may haveany possible configuration including spherical (e.g. bead), cylindrical(e.g. inside surface of a test tube or well, or the external surface ofa rod), or flat (e.g. sheet, test strip). Indirect methods may also beemployed in which the primary antigen-antibody reaction is amplified bythe introduction of a second antibody, having specificity for theantibody reactive against a PHI Protein. By way of example, if theantibody having specificity against a PHI Protein is a rabbit IgGantibody, the second antibody may be goat anti-rabbit gamma-globulinlabeled with a detectable substance as described herein.

[0213] Where a radioactive label is used as a detectable substance, aPHI Protein may be localized by radioautography. The results ofradioautography may be quantitated by determining the density ofparticles in the radioautographs by various optical methods, or bycounting the grains.

[0214] 6.2 Methods for Identifying or Evaluating Substances/Compounds

[0215] The methods described herein are designed to screen forsubstances that modulate the biological activity of a PHI Proteinincluding substances that interact with or bind with a PHI Protein, orinteract with or bind with other proteins that interact with a PHIProtein, to compounds that interfere with, or enhance the interaction ofa PHI Protein or interacting molecules in a complex, and substances thatbind to a PHI Protein or other proteins that interact with a PHIProtein. Methods are also utilized that identify compounds that bind tophip regulatory sequences.

[0216] The substances and compounds identified using the methods of theinvention include but are not limited to peptides such as solublepeptides including Ig-tailed fusion peptides, members of random peptidelibraries and combinatorialchemistry-derived molecular libraries made ofD- and/or L-configuration amino acids, polysaccharides,oligosaccharides, monosaccharides, phosphopeptides (including members ofrandom or partially degenerate, directed phosphopeptide libraries),antibodies [e.g. polyclonal, monoclonal, humanized, anti-idiotypic,chimeric, single chain antibodies, fragments, (e.g. Fab, F(ab)₂, and Fabexpression library fragments, and epitope-binding fragments thereof)],and small organic or inorganic molecules. The substance or compound maybe an endogenous physiological compound or it may be a natural orsynthetic compound.

[0217] Substances can be screened based on their ability to interactwith or bind to a PHI Protein or binding region thereof. Therefore, theinvention also provides methods for identifying substances whichinteract with or bind to PHI Proteins. Substances identified using themethods of the invention may be isolated, cloned and sequenced usingconventional techniques. A substance that interacts with a protein ofthe invention may be an agonist or antagonist of the biological orimmunological activity of a PHI Protein.

[0218] Substances which can interact with or bind to a PHI Protein maybe identified by reacting a PHI Protein or a binding region thereof,with a test substance which potentially interacts with or binds to a PHIProtein or binding region, under conditions which permit the formationof substance-PHI Protein or binding region complexes and removing and/ordetecting the complexes. The complexes can be detected by assaying forPHI Protein or binding region complexes, for free substance, or fornon-complexed PHI Proteins or binding regions. Conditions which permitthe formation of substance-PHI Protein or binding region complexes maybe selected having regard to factors such as the nature and amounts ofthe substance and the protein.

[0219] The substance-protein or binding region complex, free substanceor non-complexed proteins or binding regions may be isolated byconventional isolation techniques, for example, salting out,chromatography, electrophoresis, gel filtration, fractionation,absorption, polyacrylamide gel electrophoresis, agglutination, orcombinations thereof. To facilitate the assay of the components,antibody against PHI Proteins or a binding region thereof, or thesubstance, or labeled PHI Proteins or binding regions, or a labeledsubstance may be utilized. The antibodies, proteins, or substances maybe labeled with a detectable substance as described above.

[0220] A PHI Protein or binding region, or the substance used in themethod of the invention may be insolubilized. For example, a PHIProtein, binding region, or substance may be bound to a suitable carriersuch as agarose, cellulose, dextran, Sephadex, Sepharose, carboxymethylcellulose polystyrene, filter paper, ion-exchange resin, plastic film,plastic tube, glass beads, polyamine-methyl vinyl-ether-maleic acidcopolymer, amino acid copolymer, ethylene-maleic acid copolymer, nylon,silk, etc. The carrier may be in the shape of, for example, a tube, testplate, beads, disc, sphere etc. The insolubilized protein, bindingregion, or substance may be prepared by reacting the material with asuitable insoluble carrier using known chemical or physical methods, forexample, cyanogen bromide coupling.

[0221] It is possible to screen for agents that can be tested for theirability to treat a disease or condition characterized by an abnormalityin a signal transduction pathway by testing compounds for their abilityto affect the interaction between a PHI Protein and a binding partner,wherein the complex formed by such an interaction is part of the signaltransduction pathway.

[0222] The interaction between a PHI Protein and a binding partner maybe promoted or enhanced either by increasing production of a PHI Proteinor binding partner, or by increasing expression of a PHI Protein orbinding partner, or by promoting interaction of a PHI Protein and abinding partner, or by prolonging the duration of the interaction. Theinteraction between a PHI Protein and binding partner may be disruptedor reduced by preventing production of a PHI Protein or binding partner,or by preventing expression of a PHI Protein or binding partner, or bypreventing interaction of a PHI Protein and binding partner, orinterfering with the interaction. A method may also include measuring ordetecting various properties including the level of signal transductionand the level of interaction between a PHI Protein and a bindingpartner. Depending upon the type of interaction present various methodsmay be used to measure the level of interaction. For example, thestrengths of covalent bonds may be measured in terms of the energyrequired to break a certain number of bonds. Non-covalent interactionsmay be described as above and also in terms of the distance between theinteracting molecules. Indirect interactions may be described indifferent ways including the number of intermediary agents involved, orthe degree of control exercised over the PHI Protein relative to thecontrol exercised over the binding partner.

[0223] The invention also contemplates a method for screening byassaying for an agonist or antagonist of the interaction of, or bindingof, a PHI Protein or binding region thereof (e.g. PH domain bindingregion, IR binding region, or STAT binding region) with a substancewhich interacts with or binds with a PHI Protein or binding regionthereof (e.g. binding partners including but not limited to a PH domaincontaining protein, a PH domain, a receptor that interacts with aprotein of the IRS protein family, or STAT transcription factor). Thebasic method for evaluating if a compound is an agonist or antagonist ofthe interaction or binding of a PHI Protein or binding region thereofand a substance that binds to the protein, is to prepare a reactionmixture containing the PHI Protein or binding region thereof and thesubstance under conditions which permit the formation of substance PHIProtein or binding region complexes, in the presence of a test compound.The test compound may be initially added to the mixture, or may be addedsubsequent to the addition of the PHI Protein or binding region, andsubstance. Control reaction mixtures without the test compound or with aplacebo are also prepared. The formation of complexes is detected andthe formation of complexes in the control reaction but not in thereaction mixture, or the formation of more complexes in the controlreaction compared to the reaction mixture, indicates that the testcompound interferes with the interaction of the PHI Protein or bindingregion and substance. The reactions may be carried out in the liquidphase or the PHI Protein, binding region, substance, or test compoundmay be immobilized as described herein. The ability of a compound tomodulate the biological activity of a PHI Protein or complex of theinvention may be tested by determining the biological effects on cellsor organisms using techniques known in the art.

[0224] It will be understood that the agonists and antagonists that canbe assayed using the methods of the invention may act on one or morebinding regions on a PHI Protein or substance including agonist bindingsites, competitive antagonist binding sites, non-competitive antagonistbinding regions or allosteric sites.

[0225] The invention also makes it possible to screen for antagoniststhat inhibit the effects of an agonist of the interaction of a PHIProtein or binding region thereof, with a substance which is capable ofbinding to a PHI Protein or binding region thereof. Thus, the inventionmay be used to assay for a compound that competes for the same bindingsite of a PHI Protein.

[0226] The invention also contemplates methods for identifying compoundsthat bind to proteins that interact with a PHI Protein. Protein-proteininteractions may be identified using conventional methods such asco-immunoprecipitation, crosslinking and co-purification throughgradients or chromatographic columns. Methods may also be employed thatresult in the simultaneous identification of genes which encode proteinsinteracting with a PHI Protein. These methods include probing expressionlibraries with labeled PHI Proteins. Additionally, x-raycrystallographic studies may be used as a means of evaluatinginteractions with substances and PHI Proteins. For example, purifiedrecombinant molecules in a complex of the invention when crystallized ina suitable form are amenable to detection of intra-molecularinteractions by x-ray crystallography. Spectroscopy may also be used todetect interactions and in particular, Q-TOF instrumentation may beused. Two-hybrid systems may also be used to detect protein interactionsin vivo.

[0227] It will be appreciated that fusion proteins may be used in theabove-described methods. For example, PHI Proteins fused to aglutathione-S-transferase may be used in the methods.

[0228] It will also be appreciated that the complexes of the inventionmay be reconstituted in vitro using recombinant molecules and the effectof a test substance may be evaluated in the reconstituted system.

[0229] The reagents suitable for applying the methods of the inventionto evaluate compounds that modulate a PHI Protein may be packaged intoconvenient kits providing the necessary materials packaged into suitablecontainers. The kits may also include suitable supports useful inperforming the methods of the invention.

[0230] Peptides of the invention may be used to identify lead compoundsfor drug development. The structure of the peptides of the invention canbe readily determined by a number of methods such as NMR and X-raycrystallography. A comparison of the structures of peptides similar insequence, but differing in the biological activities they elicit intarget molecules can provide information about the structure-activityrelationship of the target. Information obtained from the examination ofstructure-activity relationships can be used to design either modifiedpeptides, or other small molecules or lead compounds that can be testedfor predicted properties as related to the target molecule.

[0231] Information about structure-activity relationships may also beobtained from co-crystallization studies. In these studies, a peptidewith a desired activity is crystallized in association with a targetmolecule, and the X-ray structure of the complex is determined. Thestructure can then be compared to the structure of the target moleculein its native state, and information from such a comparison may be usedto design compounds expected to possess desired activities.

[0232] In an aspect of the invention, a method using a PHI Protein, abinding partner, or a binding region of a PHI Protein or binding partnerto design small molecule mimetics, agonists, or antagonists is providedcomprising determining the three dimensional structure of a PHI Protein,binding partner, or binding region and providing a small molecule orpeptide capable of binding to the PHI Protein, binding partner, orbinding region. Those skilled in the art will be able to produce smallmolecules or peptides that mimic the effect of the PHI Protein, bindingpartner, or binding region and that are capable of easily entering thecell. Once a molecule is identified, the molecule can be assayed for itsability to bind a PHI Protein, binding partner, or binding region, andthe strength of the interaction may be optimized by making amino aciddeletions, additions, or substitutions or by adding, deleting orsubstituting a functional group. The additions, deletions, ormodifications can be made at random or may be based on knowledge of thesize, shape, and three-dimensional structure of the PHI Protein, bindingpartner, or binding region.

[0233] Computer modelling techniques known in the art may also be usedto observe the interaction of a PHI Protein, or binding region thereof,or agent, substance or compound identified in accordance with a methodof the invention, with an interacting molecule or binding partner (e.g.an IRS protein family member, a receptor that interacts with a proteinof the IRS protein family, or STAT transcription factor, or bindingregion thereof). (For example, Homology Insight II and Discoveryavailable from BioSym/Molecular Simulations, San Diego, Calif., U.S.A.may be used for modelling). If computer modelling indicates a stronginteraction, an agent, substance, compound or peptide can be synthesizedand tested for its ability to interfere with the binding of a PHIProtein or binding region thereof with an interacting molecule orbinding partner.

[0234] 6.3 Compositions and Treatments

[0235] PHI Proteins, peptides, and complexes of the invention, andsubstances or compounds identified by the methods described herein,antibodies, and antisense nucleic acid molecules of the invention may beused for modulating the biological activity of a PHI Protein, a complexof the invention or individual components of the complex, or a signaltransduction pathway, and they may be used in the prognostic anddiagnostic evaluation of diseases and conditions mediated by a PHIProtein, a complex of the invention or an individual component of thecomplex, or a signal transduction pathway.

[0236] PHIP potentiates the effects of insulin on gene expression andmitogenesis, transcriptional responses, DNA synthesis, actin remodeling,and glucose transporter translocation. DN PHIP mutants completely blockinsulin mediated transciptional responses and DNA synthesis. Thisinhibitory effect of DN PHIP is very specific to the insulin receptorfamily. Specifically serum stimulated transcriptional and mitogenicresponses are refractile to the effects of DN PHIP. Thus, PHIP is auseful target for therapeutic intervention in conditions or disordersassociated with insulin response.

[0237] Thus, a protein, peptide, or complex of the invention, orsubstance or compound identified by the methods described herein,antibodies, and antisense nucleic acid molecules of the invention may beadministered to a subject to prevent or treat a disorder associated withinsulin response. Examples of these disorders include but are notlimited to type 2 (non-insulin-dependent) diabetes mellitus,hyperglycemia, myotonic muscular dystrophy, acanthosis, nigricans,retinopathy, nephropathy, artherosclerotic coronary and peripheralarterial disease, and peripheral and autonomic neuropathies.

[0238] A protein, peptide, or complex of the invention or a substance orcompound identified by the methods described herein, antibodies, andantisense nucleic acid molecules of the invention may be administered toa subject to prevent or treat cancer. Cancers that may be prevented ortreated include but are not limited to adenocarcinoma, leukemia,lymphoma, melanoma, myeloma, sarcoma, and teratocarcinoma, and inparticular cancers of the adrenal gland, bladder, bone, bone marrow,brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract,heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis,prostate, salivary glands, skin, spleen, testis, thymus, thyroid, anduterus, preferably breast, prostate, colon, and ovarian carcinomas. Inparticular, cancers that may be prevented or treated in accordance withthe invention are tumors dependent on receptors that interact withproteins of the IRS protein family, preferably IGF-1 mediated cancers.

[0239] A protein, peptide, or complex of the invention or a substance,agent, or compound identified by the methods described herein,antibodies, and antisense nucleic acid molecules of the invention mayalso be useful in treating or preventing other conditions includinginfectious diseases, autoimmune diseases, immune deficiency diseases,and inflammation.

[0240] In accordance with one aspect, antibodies which bind a PHIProtein may be used directly as an antagonist or indirectly as atargeting or delivery mechanism for bringing a pharmaceutical agent tocells or tissues which express a PHI Protein. In another aspect, apeptide of the invention, or a vector expressing the complement of anucleic acid molecule encoding a PHI Protein i.e. antisenseoligonucleotide, may be administered to a subject to treat or preventcancer.

[0241] The disruption or promotion of the interaction between themolecules in complexes of the invention is also useful in therapeuticprocedures. Therefore, the invention features a method for treating asubject having a condition characterized by an abnormality in a signaltransduction pathway involving the interaction of a PHI Protein or abinding region thereof and a binding partner. In embodiments of thismethod, the interaction involves a PHI Protein or a PH domain bindingregion and a PH domain containing protein or a PH domain; a PHI Proteinor an IR binding region and a receptor that interacts with a protein ofthe IRS protein family; or, a PHI Protein or a STAT binding region, anda STAT transcription factor or a binding region thereof that interactswith a PHI Protein.

[0242] The abnormality may be characterized by an abnormal level ofinteraction between the interacting molecules in a complex of theinvention. An abnormality may be characterized by an excess amount,intensity, or duration of signal or a deficient amount, intensity, orduration of signal. An abnormality in signal transduction may berealized as an abnormality in cell function, viability, ordifferentiation state. The method involves disrupting or promoting theinteraction (or signal) in vivo, or the activity of a complex of theinvention. A compound that will be useful for treating a disease orcondition characterized by an abnormality in a signal transductionpathway involving a complex of the invention can be identified bytesting the ability of the compound to affect (i.e disrupt or promote)the interaction between the molecules in a complex. The compound maypromote the interaction by increasing the production of a PHI Protein,or by increasing expression of a PH domain, or by promoting theinteraction of the molecules in the complex. The compound may disruptthe interaction by reducing the production of a PHI Protein, preventingexpression of a PH domain, or by specifically preventing interaction ofthe molecules in the complex.

[0243] In an embodiment of the invention the PHI Proteins, peptides, andcomplexes of the invention, and substances, agents, or compoundsidentified by the methods described herein, antibodies, and antisensenucleic acid molecules of the invention are used to modulate an IGFRsignaling pathway. IGF-1 exerts pleiotropic effects on cellularprocesses through its stimulation of IGFR, a receptor tyrosine kinase.The activated IGF-1/IGFR system displays mitogenic, transforming, andanti-apoptotic properties in various cell types. Dysregulation of IGFRsignaling pathways has been found to contribute to the development andmetastatic dissemination of breast, colon, pancreatic, prostate,testicular, and ovarian carcinomas. The anti-apoptotic effect of IGF-1Rmay also mediate decreased sensitivity to chemotherapeutic drugs.

[0244] Therefore, the invention provides a method for preventing andtreating tumor cell growth and metastasis in a subject comprisingadministering a PHI Protein, peptide, complex, agent, antibody,substance, or compound of the invention, preferably a peptide of theinvention, most preferably a peptide comprising or consistingessentially of a PH domain binding region, in an amount effective toreduce the oncogenic properties of IGFR or reduce or inhibit IGF-1mediated transformation.

[0245] In another aspect of the invention, a vector expressing thecomplement of a nucleic acid molecule encoding a PHI Protein i.e.antisense oligonucleotide, may be administered to a subject in an amounteffective to treat or prevent tumor cell growth and metastasis byreducing the oncogenic properties of IGFR, or reducing or inhibitingIGF-1 mediated transformation.

[0246] In yet another aspect of the invention, a method is provided forenhancing the sensitivity of tumor cells to a pro-apoptotic agent in asubject comprising administering an effective amount of a PHI Protein,peptide, complex, or nucleic acid molecule of the invention, preferablya peptide or antisense oligonucleotide of the invention. An effectiveamount is the amount necessary to reduce the anti-apoptotic effect ofIGF-IR against pro-apoptotic agents. Examples of pro-apoptotic agentsinclude taxol, doxorubicin, etoposide, cisplatin, vinblastin,methotrexate, 5′ fluorouracil, camptothecin, mitoxanthone, cytosinearabinoside, cyclophosphamide, and paclitaxel.

[0247] A protein of the invention, peptide, complex, substance orcompound identified by the methods described herein, antibodies, andantisense nucleic acid molecules of the invention may be administered incombination with other appropriate therapeutic agents (See discussionabove re pro-apoptotic agents). The appropriate agents for use incombination therapy can be selected by a person skilled in the art basedon conventional pharmaceutical principles. The combination ofpharmaceutical agents may act synergistically to effect the treatmentand prevention of conditions described herein. Combination therapy mayenable one to achieve therapeutic efficacy with lower dosages of eachagent thereby reducing potential adverse side effects.

[0248] The proteins, substances, antibodies, complexes, peptides,agents, antibodies, and compounds can be administered to a subjecteither by themselves, or they can be formulated into pharmaceuticalcompositions for administration to subjects in a biologically compatibleform suitable for administration in vivo. By “biologically compatibleform suitable for administration in vivo” is meant a form of the activesubstance to be administered in which any toxic effects are outweighedby the therapeutic effects. Administration of a therapeutically activeamount of a pharmaceutical composition of the present invention isdefined as an amount effective, at dosages and for periods of timenecessary to achieve the desired result For example, a therapeuticallyactive amount of a substance may vary according to factors such as thedisease state, age, sex, and weight of the individual, and the abilityof antibody to elicit a desired response in the individual. Dosageregima may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

[0249] The pharmaceutical compositions or active agents containedtherein may be administered to subjects including humans, and animals(e.g. dogs, cats, cows, sheep, horses, rabbits, and monkeys).Preferably, they are administered to human and veterinary patients.

[0250] An active substance may be administered in a convenient mannersuch as by injection (subcutaneous, intravenous, etc.), oraladministration, inhalation, transdermal application, or rectaladministration. Depending on the route of administration, an activesubstance may be coated in a material to protect the substance from theaction of enzymes, acids and other natural conditions that mayinactivate the substance.

[0251] The compositions described herein can be prepared by per se knownmethods for the preparation of pharmaceutically acceptable compositionswhich can be administered to subjects, such that an effective quantityof the active substance is combined in a mixture with a pharmaceuticallyacceptable vehicle. Suitable vehicles are described, for example, inRemington's Pharmaceutical Sciences (Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., USA 1985). On thisbasis, the compositions include, albeit not exclusively, solutions ofthe active substances in association with one or more pharmaceuticallyacceptable vehicles or diluents, and contained in buffered solutionswith a suitable pH and iso-osmotic with the physiological fluids.

[0252] Vectors derived from a retrovirus, adenovirus, herpes or vacciniavirus, papovavirus, adeno-associated virus, of avian, murine, or humanorigin, or from various bacterial plasmids, may be used to delivernucleic acid molecules of the invention to a targeted organ, tissue, orcell population. Methods well known to those skilled in the art may beused to construct recombinant vectors which will express nucleic acidmolecules of the invention (e.g. nucleic acid molecules encoding PHIP, aPH domain binding region, or antisense nucleic acid molecules). (See,for example, the techniques described in Sambrook et al (supra) andAusubel et al (supra)).

[0253] The nucleic acid molecules comprising full length cDNA sequencesand/or their regulatory elements enable a skilled artisan to usesequences encoding a PHI Protein as an investigative tool in sense(Youssoufian H and H F Lodish 1993 Mol Cell Biol 13:98-104) or antisense(Eguchi et al (1991) Annu Rev Biochem 60:631-652) regulation of genefunction. Such technology is well known in the art, and sense orantisense oligomers, or larger fragments, can be designed from variouslocations along the coding or control regions.

[0254] Genes encoding a PHI Protein can be turned off by transfecting acell or tissue with vectors which express high levels of a desirednucleic acid molecule of the invention. Such constructs can inundatecells with untranslatable sense or antisense sequences. Even in theabsence of integration into the DNA, such vectors may continue totranscribe RNA molecules until all copies are disabled by endogenousnucleases. Modifications of gene expression can be obtained by designingantisense molecules, DNA, RNA or PNA, to the regulatory regions of agene encoding a protein of the invention, ie, the promoters, enhancers,and introns. Preferably, oligonucleotides are derived from thetranscription initiation site, eg, between −10 and +10 regions of theleader sequence. The antisense molecules may also be designed so thatthey block translation of mRNA by preventing the transcript from bindingto ribosomes. Inhibition may also be achieved using “triple helix”base-pairing methodology. Triple helix pairing compromises the abilityof the double helix to open sufficiently for the binding of polymerases,transcription factors, or regulatory molecules. Therapeutic uses oftriplex DNA are reviewed by Gee J E et al (In: Huber B E and B I Carr(1994) Molecular and Immunologic Approaches, Futura Publishing Co, MtKisco N.Y.).

[0255] Ribozymes are enzymatic RNA molecules that catalyze the specificcleavage of RNA. Ribozymes act by sequence-specific hybridization of theribozyme molecule to complementary target RNA, followed byendonucleolytic cleavage. The invention therefore contemplatesengineered hammerhead motif ribozyme molecules that can specifically andefficiently catalyze endonucleolytic cleavage of sequences encoding aprotein of the invention.

[0256] Specific ribozyme cleavage sites within an RNA target mayinitially be identified by scanning the target molecule for ribozymecleavage sites including the following sequences: GUA, GUU and GUC. Oncethe sites are identified, short RNA sequences of between 15 and 20ribonucleotides corresponding to the region of the target genecontaining the cleavage site may be evaluated for secondary structuralfeatures which may render the oligonucleotide inoperable. Thesuitability of candidate targets may also be determined by testingaccessibility to hybridization with complementary oligonucleotides usingribonuclease protection assays.

[0257] Methods for introducing vectors into cells or tissues includethose methods discussed herein and which are suitable for in vivo, invitro and ex vivo therapy. A vector of the invention may be administeredto a subject to correct a genetic condition characterized by a defectiveor nonexistent PHI Protein or complex of the invention. Cell populationsof a subject may also be modified by introducing altered forms of a PHIProtein or binding region thereof, or complex of the invention in orderto modulate the activity of the protein or complex. Inhibiting a PHIProtein or complex of the invention within the cells, may decrease,inhibit, or reverse a signal transduction pathway event that leads to acondition or disease. Deletion or missense mutants of a PHI Protein thatretain the ability of the PHI Protein to interact with other moleculesbut cannot retain their function in signal transduction maybe used toinhibit an abnormal, deleterious signal transduction pathway event

[0258] The invention contemplates products and methods for performingPHI Protein related gene therapy and gene transfer techniques, includingcell lines and transgenic mice (i.e. knock-out) mice for performing suchtechniques. The selection of transfected lineages, vectors, and targetsmay be confirmed in mouse models.

[0259] For ex vivo therapy, vectors may be introduced into cellsobtained from a patient and clonally propagated for autologoustransplant into the same patient (See U.S. Pat. Nos. 5,399,493 and5,437,994). Delivery by transfection and by liposome are well known inthe art. Therefore, the invention contemplates a method of administeringa nucleic acid molecule of the invention to a subject comprising thesteps of removing cells from the animal, transducing the cells with thenucleic acid molecule, and reimplanting the transduced cells into theanimal.

[0260] The invention also provides a method of administering a nucleicacid molecule of the invention using an in vivo approach comprising thesteps of administering directly to the subject the nucleic acid moleculeselected from the group of methods consisting of intravenous injection,intramuscular injection, or by catheterization and direct delivery ofthe nucleic acid molecule. The nucleic acid may encode a human proteinor peptide, and the subject to which the nucleic acid is administeredmay be a human. The nucleic acid may be administered as naked DNA or maybe contained in a viral vector. The nucleic acid molecule may beadministered in a two-component system comprising administering apackaging cell which produces a viral vector. The packaging cell may beadministered to cells in vitro.

[0261] The nucleic acid molecules of the invention may also be used inmolecular biology techniques that have not yet been developed, providedthe new techniques rely on properties of nucleotide sequences that arecurrently known, including but not limited to such properties as thetriplet genetic code and specific base pair interactions.

[0262] The invention also provides methods for studying the function ofa protein of the invention. Cells, tissues, and non-human animalslacking in expression or partially lacking in expression of a nucleicacid molecule or gene of the invention may be developed usingrecombinant expression vectors of the invention having specific deletionor insertion mutations in the gene. A recombinant expression vector maybe used to inactivate or alter the endogenous gene by homologousrecombination, and thereby create a deficient cell, tissue, or animal.

[0263] Null alleles may be generated in cells, such as embryonic stemcells by deletion mutation. A recombinant gene may also be engineered tocontain an insertion mutation that inactivates the gene. Such aconstruct may then be introduced into a cell, such as an embryonic stemcell, by a technique such as transfection, electroporation, injection,etc. Cells lacking an intact gene may then be identified, for example bySouthern blotting, Northern Blotting, or by assaying for expression ofthe encoded protein using the methods described herein. Such cells maythen be fused to embryonic stem cells to generate transgenic non-humananimals deficient in a protein of the invention. Germline transmissionof the mutation may be achieved, for example, by aggregating theembryonic stem cells with early stage embryos, such as 8 cell embryos,in vitro transferring the resulting blastocysts into recipient femalesand; generating germline transmission of the resulting aggregationchimeras. Such a mutant animal may be used to define specific cellpopulations, developmental patterns and in vivo processes, normallydependent on gene expression.

[0264] The invention thus provides a transgenic non-human mammal all ofwhose germ cells and somatic cells contain a recombinant expressionvector that inactivates or alters a gene encoding a PHI Protein. In anembodiment the invention provides a transgenic non-human mammal all ofwhose germ cells and somatic cells contain a recombinant expressionvector that inactivates or alters a gene encoding a PHI Proteinresulting in a PHI Protein associated pathology. Further the inventionprovides a transgenic non-human mammal which doe not express a PHIProtein of the invention. In an embodiment, the invention provides atransgenic non-human mammal which does not express a PHI Protein of theinvention resulting in a PHI Protein associated pathology. A PHI Proteinassociated pathology refers to a phenotype observed for a PHI Proteinhomozygous or heterozygous mutant.

[0265] A transgenic non-human animal includes but is not limited tomouse, rat, rabbit, sheep, hamster, dog, cat goat, and monkey,preferably mouse.

[0266] The invention also provides a transgenic non-human animal assaysystem which provides a model system for testing for an agent thatreduces or inhibits a PHI Protein associated pathology, comprising:

[0267] (a) administering the agent to a transgenic non-human animal ofthe invention; and

[0268] (b) determining whether said agent reduces or inhibits thepathology (e.g. PHI Protein associated pathology) in the transgenicnon-human animal relative to a transgenic non-human animal of step (a)which has not been administered the agent.

[0269] The agent may be useful in the treatment and prophylaxis ofconditions such as cancer or disorders associated with insulin responseas discussed herein. The agents may also be incorporated in apharmaceutical composition as described herein.

[0270] The activity of the proteins, peptides, complexes, substances,agents, compounds, antibodies, nucleic acid molecules, agents, andcompositions of the invention may be confirmed in animal experimentalmodel systems. Therapeutic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or with experimentalanimals, such as by calculating the ED₅₀ (the dose therapeuticallyeffective in 50% of the population) or LD₅₀ (the dose lethal to 50% ofthe population) statistics. The therapeutic index is the dose ratio oftherapeutic to toxic effects and it can be expressed as the ED₅₀/LD₅₀ratio. Pharmaceutical compositions which exhibit large therapeuticindices are preferred.

[0271] The following non-limiting examples are illustrative of thepresent invention:

EXAMPLE 1

[0272] Materials and Methods:

[0273] Antibodies: Anti-PHIP antibodies were raised against bacterialglutathione S-transferase (GST)-PHIP fusion protein (38).Anti-IRS-1^(PCT) (generated against a 16 amino acid pre C-terminalpolypeptide sequence) was purchased from Upstate Biotechnology Inc.(UBI). Monoclonal anti-HA (12CA5) and anti-myc (9E10) antibodies werefrom Babco and Santa Cruz Biotechnology, respectively. Anti-CATantibodies and mouse antibody to BrdU were purchased from 5 prime-3prime Inc. and Sigma, respectively. Rhodamine-conjugated phalloidin wasobtained from Molecular Probes. Anti transferrin receptor is purchasedfrom Zymed.

[0274] Subcellular Fractionation Assay: COS-7 cells growing in 10-cm²dishes (four dishes/condition) were transiently transfected with pCGNplasmid encoding HA-PHIP or empty vector control using calcium phosphatemethod. Twenty-four hours after transfection, cells were serumstarvedfor 12-18 hours and left untreated or treated with 100 nM ofinsulin for 5 minutes. Cell fractions were then prepared as previouslydescribed (27) with slight modifications. All procedures were performedat 0-4° C. Briefly, cells were washed and homogenized in ice-cold BufferA containing 20 mM Tris-HCl, pH 7.5, 1 mM EDTA, 255 mM sucrose, 1 mMPMSF, 10 mM NaF, 100 μM Na₃VO₄, 1 mM NaPPi, 10 μg/ml aprotinin, and 10μg/ml leupeptin for twenty strokes with a motor-driven Teflon/glasshomogenizer. The homogenate was centrifuged at 16,000×g for 20 minutes.The supernatant was centrifuged at 48,000×g for 1 hour and subsequentlyat 250,000×g to purify the low-density membrane (LDM) pellet from thehigh-density membrane (HDM). The final LDM pellet was resuspended in hot2×SDS sample buffer. The supernatant from 250,000×g centrifugation stepwas concentrated using a UFV2BGC40 filter apparatus (Millipore Corp.)which had been previously blocked with for 1 hour with 5% Tween 80 andwashed extensively with water to remove any traces of the detergentImmunoprecipitation and immunoblotting was carried out (38).

[0275] Reporter Gene Assays: COS cells were transiently transfected intriplicate samples with 5×SRE-fos luciferase reporter gene (5×SRE-LUC)and the indicated plasmids. Twenty-four hours after transfection, thecells were serum starved for 16 hours. Serum-starved cells were eitherleft untreated or treated with Mek-1 inhibitor (50 μM, NEB) for 2 hours.Cells were incubated for 10 hours with or without insulin (0.2 μM,Sigma). Luciferase activity was then analysed in cell lysates (Roche)and normalized to protein concentrations.

[0276] Microinjection Assays: Rat-1 or NIH/3T3 cells overexpressinginsulin receptor (NIH/IR) plated onto gridded glass cover slips andserum starved for 30 hours, were microinjected with the indicatedplasmids with or without 5×SRE-CAT reporter gene. For the reporterassay, 2 hours after injection, cells were treated with 0.5 μM insulinor serum (20%) as indicated and incubated for 5 hours before fixation.For the mitogenesis assay, 3 hours after injection, cells were treatedwith 10 μM BrdU (Roche), followed by addition of either 0.5 μM insulinor 20% serum. Cells were incubated for36 hours before fixation. Anti-CATand anti-BrdU antibodies were then used to analyse reporter geneexpression or DNA synthesis levels, respectively.

[0277] GLUT4myc Translocation Assay: L6^(GLUT4myc) stable cell lineswere generated as previously described (49-51). Cells growing on coverslips were transfected with the indicated constructs according to theEffectene protocol manual (Qiagen). Fourty-three hours aftertransfection, cells were deprived of serum in culture medium for threehours and were left either untreated or treated with 100 nM insulin for20 minutes. Indirect immunofluorescence for expression of cDNAconstructs and GLUT4myc translocation was carried out on intact cells aspreviously described (53). Several representative images of at leastthree separate experiments were quantified with the use of NIH (NationalInstitute of Health) image software. Raw data for GLUT4myc translocationwere expressed as fold stimulation relative to basal levels of surfaceGLUT4myc in untransfected cells. Statistical analyses were carried outwith analysis of variance (Fisher, multiple comparisons).

[0278] Actin Labeling: Growing L6^(GLUT4myc) cells on cover slips wereleft untreated or treated with 100 nM insulin for 10 minutes followingserum deprivation. Cells were rinsed with ice-cold PBS (100 mM NaCl, 1mM CaCl₂, 1 mM MgCl₂, 50 mM NaH₂PO₄/Na₂HPO₄, pH 7.4) before fixing with3% paraformaldehyde in PBS for 30 min (initiated at 4° C. for 5 minutesand shifted immediately to room temperature). The rest of the procedurewas performed at room temperature. The cells were then rinsed once withPBS, and unreacted fixative was quenched with 100 nM glycine in PBS for10 minutes. Permeabilized cells (0.1% Triton X-100 in PBS for 3 minutes)were washed quickly with PBS and blocked with 5% goat serum in PBS for10 minutes. To detect filamentous actin, cells were incubated in thedark with Rhodamine-conjugated phalloidin for 1 hour. Rinsed cover slipswere then mounted and analyzed with the Leica TCS 4D fluorescencemicroscope (Leica Mikroscoipe Systeme GmbH, Wetzlar, Germany).

[0279] Results:

[0280] In an attempt to identify functional partners of the IRS-1 PHdomain, a yeast two-hybrid screen was used in which the PH domain fromrat IRS-1 was used as a bait to screen a murine 10.5 day embryonic cDNAlibrary (5). Sequence analysis of a cDNA clone, VP1.32, which displayedthe strongest interaction with the IRS-1 PH domain, revealed an openreading frame of 201 amino acids. VP1.32 was subsequently used to screenhuman fetal brain and mouse thymus cDNA libraries (7) to obtain thecomplete coding region of human and mouse PHIP (hPHIP and mPHIP)respectively. The conceptual translation predicts a 902 amino acid (aa)protein of relative molecular weight of 104 kDa (FIG. 1A).

[0281] PHI Proteins do not share sequence homology with any knownproteins. The IRS-1 PH binding region (PBR) is located at theamino-terminus of the protein (residues 5-209). The only knownstructural motifs they possess are two bromodomains, BD1 (residues 230to 345) and BD2 (387 to 503), located in tandem in the center of themolecule (FIG. 1B). Bromodomains are conserved sequences ofapproximately 100aa that have been proposed to mediate protein-proteininteractions (8). A homology search revealed that PHIP BD sequences weremost homologous (44% identity, 61% homology) to the bromodomain of mouseCBP (CREB binding protein), a transcriptional coactivator (9). Northernblot analysis of PHIP mRNA from adult mouse tissues detected atranscript size of approximately 7.0 kb whose expression is widespread.

[0282] Western blot analysis with antibodies (Abs) raised against abacterial glutathione S-transferase (GST)-PHIP fusion protein identifieda 104 kD protein from U266 cell lysates which was not precipitated bypreimmume sera (FIG. 2A). Further analysis of PHIP expression inmammalian cell extracts revealed two forms of PHI Protein, the long 104kD form and a shorter 97 kD form (FIG. 2B). The 97 kD and 104 kDpolypeptides likely result from alternative usage of two putativetranslation initiation sites (Met1 and Met41, see FIG. 1) as ectopicexpression of full-length hPHIP containing both sites produced a doubletin PHIP immunoblots.

[0283] To recapitulate the interaction of PHIP with the IRS-1 PH domainin vitro and to assess the specificity of PH domain binding, GST-PHIP,containing residues 8-209 isolated from the yeast clone VP1.32, was usedto probe yeast cell lysates expressing hemagglutinin antigen (HA)-taggedderivatives of PH domains from IRS-1, and from unrelated signalingproteins mSos1 (Ras nucleotide exchanger), Ect-2 (Rho/Rac exchanger) andRasGAP (GTPase activating protein) (12). Interacting proteins wereanalyzed by western blotting with anti-HA Abs (FIG. 2C). WhereasGST-PHIP bound to the IRS-1 PH domain, there was no discernableassociation with PH domains of other proteins, suggesting that PHIP mayfunction as a specific ligand of the IRS-1 PH domain.

[0284] Next, to examine whether a functional PH domain or a smallermotif within the domain is responsible for PHIP binding, we generatedthree independent mutants of the IRS-1 PH domain that disrupt the PHfold: PH^(NT) encompasses the first half of the IRS-1 PH domain,spanning residues 3-67, PH^(CT) comprises the C-terminal residues55-133, and PH^(W106A) defines a mutant where the Tryptophan at position106, a residue conserved in all PH domains, was changed to Ala Asexpected, all three PH-domain mutants expressed transiently in COS-1cells did not detectably associate with GST-PHIP, consistent with thenotion that an intact PH domain is required for PHIP binding (FIG. 2D).

[0285] To investigate the interaction of PHIP and IRS-1 in vivo, lysatesfrom NIH/IR cells (NIH3T3 cells overexpressing the insulin receptor)were immunoprecipitated with anti-IRS-1 Abs directed against theC-terminus of IRS-1. Endogenous PHIP was found to associate with IRS-1in both unstimulated and insulin-treated cells. (FIG. 2E, lanes 1 and2). By contrast, when antibodies directed against the IRS-1 PH domainwere used in similar co-immunoprecipitation assays, no interaction wasdetected, confirming that structural determinants within the PH domainof IRS-1 confer binding to PHIP. PHIP was also detected in anti-IRS-2immunoprecipitates (FIG. 2E, lane 7), consistent with the observationthat IRS-1 and IRS-2 PH domains have been shown to be functionallyinterchangeable in promoting substrate recognition by the IR (4). Thus,PHIP may have a conserved function in recruiting members of the IRSprotein family to activated IR complexes. To evaluate the effect ofinsulin binding on regulating PHIP/IRS-1 PH interactions, antibodiesdirected against the PHIP PH binding region (PBR) were used, as anindirect score for measuring conformational changes in this regioninduced upon insulin stimulation. PHIP/IRS-1 immune complexes wereobserved only in the insulin-treated cells using the PHIP Abs inimmunoprecipitation assays (FIG. 2F). These results indicate thatalthough PHIP and IRS-1 proteins are stably associated in cells, contactsites between the PHIP PBR region and the IRS-1 PH domain are regulatedby insulin. This raises the possibility that structural changes at thePHIP PBR/IRS-1 PH interface observed upon insulin stimulation, mayinfluence the interactions of the IRS-1 PTB with the phosphorylatedinsulin receptor. Consistent with this idea, substitution of the IRS-1PH domain with heterologous PH domains from (adrenergic receptor kinase,and phospholipase C (impairs binding of the tandem PTB domain tophosphorylated NPEY peptides (4).

[0286] Whether PHIP functions as a substrate of the IR in vivo wasexamined, as there are several potential tyrosine phosphorylation sitesin the PHIP sequence. Anti-phosphotyrosine immunoblots of PHIP failed toshow any discernible IR-regulated phosphorylation of PHIP (FIG. 2F).PHIP however inducibly associated with a prominent 103 kDaphosphoprotein (i.e. STAT3).

[0287] One of the early signaling events initiated by the IR isactivation of MAP kinase (14). Moreover, in many cells, IRS-1 has beenshown to be an upstream mediator MAP kinase activation during insulinstimulation. To evaluate the effect of PHIP on IRS-1-mediated MAP kinaseactivation, hemagglutinin antigen (HA)-tagged PHIP constructs were usedthat encode the IRS-1 PHIP PBR region alone (residues 8-209) which waspredicted to function in a dominant inhibitory fashion by competing withthe endogenous PHIP for the IRS-1 PH domain. Indeed, ectopicallyexpressed dominant-negative PHIP (DN-PHIP) binds to endogenous IRS-1 inboth untreated and insulin-stimulated cell lysates (FIG. 4A, panel 3).COS cells were co-transfected with DN-PHIP and HA-tagged p44^(MAPK) andanti-HA immune complexes from serum starved and insulin-stimulated celllysates were subjected to an in vitro kinase assay using myelin basicprotein (MBP) substrate. As shown in FIG. 4D, insulin-stimulated MAPkinase activation was reduced to basal levels by DN-PHIP expression. Asexpected, SHC phosphorylation remained retractile to the effects ofDN-PHIP, suggesting that in these cells the PHIP/IRS-1 signaling pathwayis essential for promoting MAP kinase activation during insulinstimulation. To evaluate the involvement of PHIP in insulin mediatedtranscriptional responses, its ability to induce transcription from asynthetic reporter, 5×SRE-LUC, which contains five copies of the serumresponsive element (SRE) from the human c-fos promoter (15) was tested.COS-1 cells transiently transfected with the 5×SRE-LUC reporter gene andincreasing amounts of hPHIP led to a dose-dependent increase in basallevels of transcription in untreated cells which was further enhanced byresponse to insulin (FIG. 3A). In order to investigate the relativeimportance of the MAP kinase pathway as a downstream effector of PHIPmediated gene expression, the Mek1 inhibitor, PD98059, was used to blockMAP kinase activation (17). The complete sensitivity of ligand-dependentPHIP SRE-LUC transactivation to PD98059, suggests that the MAP kinasecascade is an important component of insulin-stimulated PHIPtranscriptional responses.

[0288] To determine whether IRS-1 PH binding is required for PHIP'sability to potentiate insulin responses, the effect of overexpressingthe N-terminal IRS-1 PH domain (IRS-PH) on PHIP-stimulated SRE-LUCtransactivation was evaluated. Increasing expression of IRS-PHprogressively blocked the PHIP signal, indicating thatPH-domain-directed interaction between PHIP and IRS-1 is required forPHIP-induced gene expression (FIG. 3B). Overexpression of IRS-1 overcamethis inhibition in a dose-dependent manner, indicating that the IRS-1 PHdomain competes with wild type IRS-1 for PHIP complex formation (FIG.3C).

[0289] To further establish the physiological significance of IRS-1/PHIPinteractions for gene expression, HA-tagged DN-PHIP was microinjectedinto insulin-responsive Rat-1 fibroblasts. Insulin and serum treatmentof parental Rat-1 fibroblasts microinjected with the reporter plasmid5×SRE-CAT (chroramphenicol acetyltransferase) resulted in expression ofthe CAT protein readily detectable by immunofluorescence staining withanti-CAT Abs. However, cells co-injected with the construct expressingHA-tagged DN-PHIP blocked insulin-but not serum-stimulated CATexpression, indicating that PHIP is a critical component of thesignaling pathway used by IR to regulate gene expression. This isconsistent with the finding that DN-PHIP has a pronounced inhibitoryeffect on MAP kinase activation in insulin-treated cells. Co-injectionof IRS-1 with DN-PHIP, fully restored SRE-CAT expression furthersupporting the idea that IRS-1 lies downstream of PHIP in the insulinsignaling pathway.

[0290] Previous studies have demonstrated that the growth stimulatoryeffects of insulin are dependent on IRS-1 (19, 45). To examine the roleof PHIP in IRS-1 mediated mitogenic signaling, DN-PHIP was microinjectedinto fibroblasts overexpressing IR (NIH/IR) cells to study its effect on5-bromodeoxyuridine (BrdU) incorporation into newly synthesized DNA.Whereas the growth stimulatoy effects of serum were not affected bymicroinjection of DN-PHIP, insulin-induced stimulation of DNA synthesiswas markedly attenuated in NIH/IR cells injected with DN-PHIP,consistent with the notion that PHIP/IRS-1PH interactions are essentialin promoting the proliferative actions of insulin.

[0291] In order to establish the mechanism by which DN-PHIP inhibitsinsulin-mediated gene expression and DNA synthesis, whether DN-PHIP hadthe ability to disrupt IRS-1 phosphorylation in response to insulin wasexamined. Transient expression of DN-PHIP, but not fill length PHIP,significantly impaired IRS-1 tyrosine phosphorylation (>5-fold) ininsulin-treated cells. To ascertain whether the reduction in IRS-1phosphorylation occurred through interference with receptor function,changes were looked for in phosphotyrosine levels of immunoprecipitatedIR and Shc, a direct substrate of the activated IR. The resultsdemonstrate that diminution of IRS-1 tyrosine phosphorylation levels wasnot attributable to inhibition of IR kinase activity in at least twocell backgrounds. Next the association of PHIP with the insulin receptorwas examined. Co-immunoprecipitation assays failed to detect PHIP in IRimmune complexes.

[0292] Similar results have previously been reported for the associationof the IR with either IRS-1 or the SHC adaptor, suggesting thatIR/effector interactions are weak or transient in nature, and notdetected in receptor immune complexes (73-75).

[0293] One of the main metabolic effects of insulin action on fat andmuscle cells is the regulation of glucose uptake by inducing theredistribution of the glucose transporter, GLUT4, from intracellularcompartments to the plasma membrane (44). Activation of the p85/p110isoform of PI 3-kinase through its recruitment to phosphotyrosine siteson IRS-1 is a necessary component of insulin-stimulated GLUT4translocation (45, 46). The role of IRS-1 in this process is somewhatcontroversial, with some studies indicating that IRS-1 tyrosinephosphorylation can be blocked without any effect on GLUT4 transport(47-48). In order to examine whether PHIP/IRS-1 complexes participate inthe signal transduction pathway linking the IR to GLUT4 traffic inmuscle cells, L6 myoblasts stably expressing a myc-tagged GLUT4construct (L6GLUT4myc) (49-51) were transiently transfected with eitherwild-type or dominant-interfering forms of PHIP or IRS-1. Co-expressionof green fluorescent protein (GFP) cDNA was used to facilitaterecognition of transfected cells. As previously shown, insulin treatmentof L6GLUT4myc myoblasts generates a two-fold gain in cell-surfaceGLUT4myc detected by immunofluorescence labeling of the exofacial mycepitope (52, 53). Ectopic expression of DN-PHIP caused a near completeinhibition of insulin-dependent GLUT4myc membrane translocation (>90%),in a manner identical to that observed with a dominant-negative mutantof the p85 subunit of PI 3-kinase (Δp85) (45, 54). The effect of DN-PHIPwas specific for the insulin-stimulated state, as the content of cellsurface GLUT4myc in unstimulated cells was not altered by the PHIPmutant. Expression from a plasmid encoding the IRS-1 PH domain alsocaused a significant reduction in insulin-dependent GLUT4myctranslocation, albeit somewhat less robust (60%) than that induced byDN-PHIP. The incomplete inhibition may be accounted for in part by thepresence of other IRS proteins that may partially substitute for IRS-1function. By contrast, neither full-length PHIP nor full-length IRS-1caused any measurable change in GLUT4myc redistribution. Taken together,these results support the idea that PHIP/IRS-1 complex formation isnecessary but not sufficient in promoting the metabolic effects ofinsulin in muscle cells.

[0294] Recent evidence points to the potential participation of theactin microfilament network in promoting not onlyinsulin-dependentredistribution of PI 3-kinase to GLUT4-containingvesicles but also in mobilizing GLUT4 to the cell surface (55-57). Inlight of the fact that previous reports have demonstrated therequirement of functional IRS-1 for insulin-stimulated actincytoskeletal rearrangement (47), the role of PHIP in this process wasexamined. Rhodamine-conjugated phalloidin was used to detect changes inthe pattern of filamentous actin in L6GLUT4myc cells ectopicallyexpressing either wild-type PHIP or DN-PHIP. Whereas actin staining inthe basal state exhibits a filamentous pattern that runs along thelongitudinal axis of the cell, a marked reorganization of actin intodense structures throughout the myoplasm was observed upon insulinstimulation. This effect was dramatically decreased by the expression ofDN-PHIP but not by the empty vector or wild-type PHIP. Intriguingly,overexpression of wild-type PHIP appeared to induce remodeling of theactin cytoskeleton even under basal conditions. Taken together, theobservations clearly implicate PHIP in the regulation ofinsulin-dependent processes that promote cytoskeletal remodeling andaccompany incorporation of GLUT4 vesicles at the plasma membrane surfaceof muscle cells.

[0295] Cellular compartmentalization and intracellular trafficking ofIRS-1 are essential in its ability to elicit insulin responses (30).Previous reports have shown that under basal conditions, insulinreceptors are predominantly localized at the plasma membrane, whileabout two-thirds of the IRS-1 molecules associate with the LDM, andone-third are distributed within the cytoplasm (27-30, 58). Biochemicalanalyses of the LDM from cultured adipocytes indicates that IRS-1 doesnot associate with membranes in this fraction, but rather with whatappears to be an insoluble protein matrix highly enriched incytoskeletal elements that include actin (57, 59). Given that PHIPstably associates with IRS-1, whether PHIP co-localizes with IRS-1 inthe LDM was examined. Immunoblot analysis of endogenous and ectopicallyexpressed IRS-1 in L6 myoblasts failed to reveal strong immunoreactivesignals, so a heterologous system was used to examine the cellulardistribution of PHIP and IRS-1. Immunofluorescence microscopy of COS-7cells indicated that PHIP and IRS-1 are immunolocalized in the cytoplasm(data not shown). Moreover, as demonstrated in FIG. 5A, subcellularfractionation of COS-7 cells revealed that tyrosine phosphorylated IRS-1is distributed between the LDM fraction and the cytosol, consistent withthe distribution of IRS-1 previously observed in adipocytes.Significantly, HA-PHIP ectopically expressed in COS-7 cells was foundco-localized with IRS-1 primarily in the LDM fraction. (FIG. 5A).Furthermore, insulin treatment did not detectably alter the subcellularlocation of PHIP from the LDM to the cytosol. Therefore, PHIP mayrepresent the putative IRS-1 binding component that serves to tetherIRS-1 proteins, through its association with the IRS-1 PH domain, tocytoskeletal elements in the LDM compartment.

[0296] Biochemical studies in 3T3-L1 adipocytes indicate that IRS-1 ispreferentially tyrosine phosphorylated in the LDM compartment (27, 58).Furthermore, insulin treatment induces a pronounced retardation in theelectrophoretic mobility of IRS-1, due to hyperphosphorylation onserine/threonine (S/T) residues, which triggers the release of IRS-1from the LDM to the cytosol(27, 28, 58, 60, and 61). This has led to thehypothesis that S/T phosphorylation of IRS-1 modulates IRS-1/LDMinteractions. Given that PHIP segregates with IRS-1 in the LDM and isknown to regulate IR-mediated IRS-1 tyrosine phosphorylation, the effectof PHIP overexpression on IRS-1 S/T phosphorylation was tested bymonitoring the electrophoretic properties of IRS-1 by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Under basalconditions, increasing amounts of ectopically expressed PHIP induced adose-dependent increase in the electrophoretic mobility of IRS-1 (FIG.5B). Given that hypophosphorylated forms of IRS-1 display increasedassociation with LDM fractions (28, 58), the data suggest that PHIPoverexpression may modulate a S/T phosphorylation event that enhancessequestration of IRS-1 to the LDM compartment. By contrast, acuteinsulin stimulation(5 min) of PHIP transfectants, produced a significantretardation in the mobility of IRS-1, consistent with an increase in thephospho-S/T content of IRS-1. This shift is typically observed withprolonged insulin treatment (15-60 min) (27, 58, and 62). Importantly,the amount of tyrosine phosphorylated IRS-1 remained fairly constant ifnot slightly increased in the highest PHIP expressors, when normalizedfor protein levels. These findings indicate that PHIP-dependentphosphorylation of IRS-1 S/T residues may elicit a positive regulatoryeffect on downstream signaling events. A recent study revealed thatphosphorylation of serine residues within the PTB domain of IRS-1 byinsulin-stimulated PKB, protects IRS-1 proteins from the rapid action ofprotein tyrosine phosphatases, and enables serine-phosphorylated IRS-1proteins to maintain their tyrosine-phosphorylated active conformation(63).

[0297] Discussion

[0298] These results are the first to identify a protein ligand of theIRS-1 PH domain with a clear physiological role in both insulin-mediatedmitogenic and metabolic responses. A dominant negative N-terminaltruncation mutant of PHIP has been described, DN-PHIP, which potentlyinhibits insulin-induced transcriptional and proliferative responses.This inhibition is remarkably specific for insulin, as serum inducedtransactivation and DNA synthesis is unaffected by DN-PHIP. Moreoverthis inhibition is overcome by co-expression of IRS-1. Taken together,the data indicate that regions of PHIP implicated in interactions withthe IRS-1 PH domain can disengage IR from IRS-1 proteins andsubsequently decrease sensitivity to growth-promoting responses ofinsulin.

[0299] The role of IRS-1 proteins in insulin action on glucose transportis less clear. Several lines of evidence support the involvement ofIRS-1 for GLUT4 externalization For example, expression of anti-senseribozyme directed against rat IRS-1 significantly reduces GLUT4translocation to the plasma membrane of rat adipose cells in response toinsulin (64). Moreover, mutations of IR Tyr960 which do not alterreceptor kinase activity, but are critical for IRS-1 binding andphosphorylation, abolish glucose transport (65-67). However, in contrastto these findings, other reports indicate that microinjection ofanti-IRS-1 antibodies or expression of dominant inhibitory PTB domainsof IRS-1 are able to block the mitogenic effects of insulin infibroblasts but not GLUT4 trafficking in cultured adipocytes (47, 68).Interpretation of the results in adipocytes, is confounded by theobservation that glucose uptake proceeds unabated in IRS-1PTB-expressing cells, despite a near complete inhibition of not onlyIRS-1 tyrosine phosphorylation but of IR kinase activity (68).

[0300] In this current study, strong support is provided for theinvolvement of PHIP/IRS-1 complexes in glucose transporter translocationin muscle cells. The use of PHIP or IRS-1 constructs known to interferewith efficient IR/IRS-1 protein interaction and hence productive signaltransduction from IRS-1 to PI 3-kinase, are capable of interfering withinsulin-stimulated GLUT4 translocation in L6 myoblasts. Moreover, thisinhibition does not coincide with changes in the autophosphorylationstatus of the IR. The data also indicate that overexpression of eitherPHIP or IRS-1 alone in muscle cells was not sufficient in promotingtransport of GLUT4 to plasma membrane surfaces. This is consistent withother observations indicating that activation of IRS-1-associatedsignaling effectors such as PI 3-kinase, although necessary, is notsufficient for GLUT4 activation. Notably, growth factors such as PDGFand IL4 can activate PI 3-kinase as efficiently as insulin yet fail tostimulate glucose transport in insulin-sensitive cells (69, 70). Onepossible explanation is that additional PHIP/IRS-1/PI3-kinase-independent pathways are required to coordinate GLUT4intracellular routing. Indeed, recent evidence points to a novelinsulin-responsive pathway that recruits flotillin/CAP/CBL complexes toIR-associated lipid rafts in the plasma membrane, an event which isthought to potentiate GLUT4 docking to the cell surface followinginsulin receptor activation (71).

[0301] A commonly held view to account for the specificity of insulinsignaling on glucose transport, is that biological specificity isconferred at the level of cellular compartmentalization of signalingintermediates. Indeed, subcellular fractionation studies in 3T3-L1adipocytes and IR-overexpressing CHO cells, revealed that activated PI3-kinase complexes are found predominantly in the LDM following insulintreatment , whereas activation of PI 3-kinase in response to PDGF in thesame cells, occurs at the plasma membrane (58, 59). Analogously,differences in the pattern of intracellular distribution have beendocumented among the four members of the IRS protein family (IRS 1-IRS4)and may account for differences in their ability to engage downstreamsignaling elements which may ultimately contribute to their functionalspecifity in vivo (28, 29, 72). In support of the idea that subcellularcompartmentalization is central to IRS signal transduction, it has beendemonstrated that altered trafficking and tight membrane association ofCAAX-modified IRS-1 dramatically impairs insulin signaling. Moreover,based on the present studies, colocalization of PHIP with IRS-1 in theLDM compartment may be a key determinant in the selectivity andspecificity of PHIP inhibitory action on IR signaling.

[0302] The molecular basis for sequestration of IRS-1 to internal lowdensity microsomal fractions remains unclear. One obvious candidate isthe IRS-1 PH domain. Previous studies have demonstrated the importanceof PH domains in targeting proteins to cellular membranes by binding tophospholipids (33). However, the majority of these interactionsare weakand non-selective, suggesting the presence of specific cellular ligandsfor PH domain targeting function.

[0303] PHIP may serve as a molecular scaffold to sequester IRS-1 tocytoskeletal elements in the LDM. There are several observations thatsupport this. First, the majority of IRS-1 is not anchored to membranecomponents but rather to an insoluble protein matrix in the LDM. Thisindicates that IRS-1 must be maintained at this location by specificassociation with other protein (s). Second, this Triton-insolublefraction of the LDM contains a significant fraction of the actincytoskeleton as determined by sedimentation analysis and electronmicroscopy (57, 59). Third, PHIP is stably associated and cofractionateswith IRS-1 in the LDM under basal conditions. Finally, ectopicexpression of PHIP can induce filamentous actin reorganization atdiscrete sites in the myoplasm, implicating PHIP in the spatial controlof actin assembly. Taken together these data suggest that PHIP, throughdirect association with the IRS-1 PH domain may regulate tethering ofIRS-1 molecules to the cytoskeletal component in the LDM. Thus PHIP maybe important for the preassembly of IRS-1 proteins onto a cytoskeletalscaffold that is in close apposition to IR-enriched lipid rafts,providing a kinetic advantage in IRS-1 substrate recognition followingreceptor ligation. Moreover, the observation that ectopic expression ofPHIP modulates the S/T phosphorylation status of IRS-1 proteins, amechanism known to regulate the intracellular routing of IRS-1 betweenthe LDM and cytosol, suggests that PHIP may also be involved in temporaldesensitization or dampening of insulin signals by terminating access ofIRS-1 to the IR. The insulin-regulatable effect of PHIP overexpressionon the phospho-S/T content of IRS-1 could be due to the activation of akinase and/or inhibition of a serine/threonine phosphatase acting onIRS-1.

[0304] In conclusion, PHIP represents a novel physiological proteintarget of the IRS-1 PH domain, that may contribute to IR coupling byregulating the spatial-temporal subcellular localization of IRS-1protein complexes, which plays a pivotal role in the specificity andselectivity of IRS-1 function.

EXAMPLE 2

[0305] Mutants of DN-PHIP were made in both GST and HIS tagged vectors.The sequences of the mutants are as follows: DN-mPHIP (aa 5-209)RLAVGELTENGLTLEEWLPSAWITDTLPRRCPFVPQMGDEVYYFRQGHEAYVEMARKNKIYSI (SEQ IDNO: 66) NPKKQPWHKMLEREQELMKIVGIKYEVGLPTLCCLKLAFLDPDTGKLTGGSFTMKYHDMPDVIDFLVLRQQFDDAKYRRWNIGDRFRSVIDDAWWFGTIESQEPLQPEYPDSLFQCYNVCWDNGDTEKMSPWDMELIPNNAV Mutant DN-mPHIP #1 (aa 5-170)RLAVGELTENGLTLEEWLPSAWITDTLPRRCPFVPQMGDEVYYFRQGHEAYVEMARKNKIYSI (SEQ IDNO: 67) NPKKQPWHKMELREQELMKIVGIKYEVGLPTLCCLKLAFLDPDTGKLTGGSFTMKYHDMPDVIDFLVLRQQFDDAKYRRWNIGDRFRSVIDDAWWFGTIESQE Mutant DN-mPHIP #2 (aa 19-170)EEWLPSAWITDTLPRRCPFVPQMGDEVYYFRQGHEAYVEMARKNKIYSINPKKQPWHKMELR (SEQ IDNO:68) EQELMKIVGIKYEVGLPTLCCLKLAFLDPDTGKLTGGSFTMKYHDMPDVIDFLVLRQQFDDAKYRRWNIGDRFRSVIDDAWWFGTIESQE

[0306] The mutants became insoluble when expressed in bacteria. Thisindicates that these small N- and C-terminal deletions perturb thestructural integrity of the PBR protein module.

[0307] The present invention is not to be limited in scope by thespecific embodiments described herein, since such embodiments areintended as but single illustrations of one aspect of the invention andany functionally equivalent embodiments are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description and accompanying drawings.Such modifications are intended to fall within the scope of the appendedclaims.

[0308] All publications, patents and patent applications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the cell lines, vectors, methodologies etc.which are reported therein which might be used in connection with theinvention. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

[0309] It must be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference to“a host cell” includes a plurality of such host cells, reference to the“antibody” is a reference to one or more antibodies and equivalentsthereof known to those skilled in the art, and so forth.

References and Notes

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[0314] 5. The PH domain from rat IRS-1 (residues 3-133) was fused to theLexA binding domain within the BTM116 vector and used as a ‘bait’ toscreen for interacting clones from a mouse 10.5 day embryoniccomplementary DNA (cDNA) library fused with the VP16-activation domain(6). A total of 89 positive clones were identified, most of which wererepresented at least twice, indicating that the screen was saturated.The clone which displayed the strongest interaction with the IRS-1 PHdomain, VP1.32 was representative of 18/89 positive clones.

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[0384] 75. Yenush, L., Fernandez, R., Myers, M. G. J., Grammer, T. C.,Sun, X. J., Blenis, J., Pierce, J. H., Schlessinger, J., and White, M.F. (1996) Mol Cell Bio May 16, 1996 2509-2517.

1 77 1 2835 DNA Homo sapiens 1 agattggctg tgggagaact aactgaaaatggtttgacat tagaagaatg gttgccatca 60 acatggatta cagataccat tccccgaagatgtccatttg tgccacagat gggtgatgag 120 gtttattatt tccgacaagg acatgaagcctatgtcgaaa tggcccggaa aaataaaata 180 tatagtatca atcccaaaaa acaaccatggcataaaatgg agctacggga acaagaactt 240 atgaaaatag ttggcataaa gtatgaagtgggattaccta ccctttgctg ccttaaactt 300 gcttttctag atcctgatac tggtaaactgactggtggat catttaccat gaaataccat 360 gatatgcctg acgtcataga ttttctagtcttgagacaac aatttgatga tgcaaaatac 420 aggcgatgga atataggtga ccgcttcaggtctgtcatag atgatgcctg gtggtttgga 480 acaatcgaaa gccaggaacc tcttcaacttgagtaccctg atagtctgtt tcaatgctac 540 aatgtttgct gggacaatgg agatacagaaaagatgagtc cttgggatat ggagcttata 600 cctaataatg ctgtatttcc tgaagaactaggtaccagtg ttcctttaac tgatggtgag 660 tgcagatcac taatctataa acctcttgatggagaatggg gtaccaatcc cagggatgaa 720 gaatgtgaaa gaattgtggc aggaataaaccagttgatga cactagatat tgcctcagca 780 tttgtggccc ccgtggatct gcaagcctatcccatgtatt gcacagtagt ggcatatcca 840 acggatctaa gtacaattaa acaaagactggaaaacaggt tttacaggcg ggtttcttcc 900 ctaatgtggg aagttcgata tatagagcataatacacgaa catttaatga gcctggaagc 960 cctattgtga aatctgctaa attcgtgactgatcttcttc tacattttat aaaggatcag 1020 acttgttata acataattcc actttataattcaatgaaga agaaagtttt gtctgattct 1080 gaggatgaag agaaagatgt tgatgtgccaggaacttcta ctcgaaaaag gaaggaccat 1140 cagcgtagaa gaagattacg taatagagcccagtcttacg atattcaagc atggaagaac 1200 cagtgtgaag aattgttaaa tctcatatttcaatgtgaag attcagagcc tttccgtcag 1260 ccggtagatc tccttgaata tccagactacagagacatca ttgacactcc aatggatttt 1320 gctaccgtta gagaaacttt agaggctgggaattatgagt caccaatgga gttatgtaaa 1380 gatgtcagac ttattttcag taattccaaagcatatacac caagcaaaag atcaaggatt 1440 tacagcatga gtttgcgcct gtctgctttctttgaagaac acattagttc agttttatca 1500 gattataaat ctgctcttcg ttttcataaaagaaatacca taaccaaaag gaggaagaaa 1560 agaaacagaa gcagctctgt ttccagtagtgctgcatcaa gccctgaaag gaaaaaaagg 1620 atcttaaaac cccagctaaa atcagaaagctctacctctg cattctctac acctacacga 1680 tcaataccgc caagacacaa tgctgctcagataaacggta aaacagaatc tagttctgtg 1740 gttcgaacca gaagcaaccg agtggttgtagatccagttg tcactgagca accatctact 1800 tcttcagctg caaagacttt tattacaaaagctaatgcat ctgcaatacc agggaaaaca 1860 atactagaga attctgtgaa acattccaaagctttgaata ctctttccag tcctggtcaa 1920 tccagtttta gtcatggcac taggaataattctgcaaaag aaaacatgga aaaggaaaag 1980 ccagtcaaac gtaaaatgaa gtcatctgtactcccaaagg cgtccactct ttcaaagtca 2040 tcagctgtca ttgagcaagg agattgtaagaacaacgctc ttgtaccagg aaccattcaa 2100 gtaaatggcc atggaggaca gccatcaaaacttgtgaaga ggggacctgg aaggaaacct 2160 aaagtagaag ttaataccaa tagtggtgaaattatacaca agaaaagggg tagaaagccc 2220 aaaaagctac agtatgcaaa gccagaagatttagagcaaa ataatgtgca tcccatcaga 2280 gatgaagtac ttccttcttc aacatgcaattttctttctg aaactaataa tgtaaaggaa 2340 gatttgttac agaaaaagaa tcgtggaggtaggaagccca aaaggaagat gaagacacaa 2400 aaattagatg cagatctcct agtccctgcaagtgtcaaag tgttaaggag aagtaacccg 2460 aaaaaaatag atgatcctat agatgaggaagaagagtttg aagaactcaa aggctctgaa 2520 ccccacatga gaactagaaa tcaaggtcgaaggacagctt tctataatga ggatgactct 2580 gaagaggagc aaaggcagct gttgttcgaagacacctctt taacttttgg aacttctagt 2640 agaggacgag tccgaaagtt gactgaaaaagcaaaagcta atttaattgg ttggtaactt 2700 gtaccaaaat attttacttc aaaatctataaagcaggtac agttaaggaa taagtaggac 2760 taaggcttct gcttccttgc tgctgtggtggagtagggaa tgttatgatt tgatttgcaa 2820 aaaaaaaaaa aaaag 2835 2 898 PRTHomo sapiens 2 Arg Leu Ala Val Gly Glu Leu Thr Glu Asn Gly Leu Thr LeuGlu Glu 1 5 10 15 Trp Leu Pro Ser Thr Trp Ile Thr Asp Thr Ile Pro ArgArg Cys Pro 20 25 30 Phe Val Pro Gln Met Gly Asp Glu Val Tyr Tyr Phe ArgGln Gly His 35 40 45 Glu Ala Tyr Val Glu Met Ala Arg Lys Asn Lys Ile TyrSer Ile Asn 50 55 60 Pro Lys Lys Gln Pro Trp His Lys Met Glu Leu Arg GluGln Glu Leu 65 70 75 80 Met Lys Ile Val Gly Ile Lys Tyr Glu Val Gly LeuPro Thr Leu Cys 85 90 95 Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr GlyLys Leu Thr Gly 100 105 110 Gly Ser Phe Thr Met Lys Tyr His Asp Met ProAsp Val Ile Asp Phe 115 120 125 Leu Val Leu Arg Gln Gln Phe Asp Asp AlaLys Tyr Arg Arg Trp Asn 130 135 140 Ile Gly Asp Arg Phe Arg Ser Val IleAsp Asp Ala Trp Trp Phe Gly 145 150 155 160 Thr Ile Glu Ser Gln Glu ProLeu Gln Leu Glu Tyr Pro Asp Ser Leu 165 170 175 Phe Gln Cys Tyr Asn ValCys Trp Asp Asn Gly Asp Thr Glu Lys Met 180 185 190 Ser Pro Trp Asp MetGlu Leu Ile Pro Asn Asn Ala Val Phe Pro Glu 195 200 205 Glu Leu Gly ThrSer Val Pro Leu Thr Asp Gly Glu Cys Arg Ser Leu 210 215 220 Ile Tyr LysPro Leu Asp Gly Glu Trp Gly Thr Asn Pro Arg Asp Glu 225 230 235 240 GluCys Glu Arg Ile Val Ala Gly Ile Asn Gln Leu Met Thr Leu Asp 245 250 255Ile Ala Ser Ala Phe Val Ala Pro Val Asp Leu Gln Ala Tyr Pro Met 260 265270 Tyr Cys Thr Val Val Ala Tyr Pro Thr Asp Leu Ser Thr Ile Lys Gln 275280 285 Arg Leu Glu Asn Arg Phe Tyr Arg Arg Val Ser Ser Leu Met Trp Glu290 295 300 Val Arg Tyr Ile Glu His Asn Thr Arg Thr Phe Asn Glu Pro GlySer 305 310 315 320 Pro Ile Val Lys Ser Ala Lys Phe Val Thr Asp Leu LeuLeu His Phe 325 330 335 Ile Lys Asp Gln Thr Cys Tyr Asn Ile Ile Pro LeuTyr Asn Ser Met 340 345 350 Lys Lys Lys Val Leu Ser Asp Ser Glu Asp GluGlu Lys Asp Val Asp 355 360 365 Val Pro Gly Thr Ser Thr Arg Lys Arg LysAsp His Gln Arg Arg Arg 370 375 380 Arg Leu Arg Asn Arg Ala Gln Ser TyrAsp Ile Gln Ala Trp Lys Asn 385 390 395 400 Gln Cys Glu Glu Leu Leu AsnLeu Ile Phe Gln Cys Glu Asp Ser Glu 405 410 415 Pro Phe Arg Gln Pro ValAsp Leu Leu Glu Tyr Pro Asp Tyr Arg Asp 420 425 430 Ile Ile Asp Thr ProMet Asp Phe Ala Thr Val Arg Glu Thr Leu Glu 435 440 445 Ala Gly Asn TyrGlu Ser Pro Met Glu Leu Cys Lys Asp Val Arg Leu 450 455 460 Ile Phe SerAsn Ser Lys Ala Tyr Thr Pro Ser Lys Arg Ser Arg Ile 465 470 475 480 TyrSer Met Ser Leu Arg Leu Ser Ala Phe Phe Glu Glu His Ile Ser 485 490 495Ser Val Leu Ser Asp Tyr Lys Ser Ala Leu Arg Phe His Lys Arg Asn 500 505510 Thr Ile Thr Lys Arg Arg Lys Lys Arg Asn Arg Ser Ser Ser Val Ser 515520 525 Ser Ser Ala Ala Ser Ser Pro Glu Arg Lys Lys Arg Ile Leu Lys Pro530 535 540 Gln Leu Lys Ser Glu Ser Ser Thr Ser Ala Phe Ser Thr Pro ThrArg 545 550 555 560 Ser Ile Pro Pro Arg His Asn Ala Ala Gln Ile Asn GlyLys Thr Glu 565 570 575 Ser Ser Ser Val Val Arg Thr Arg Ser Asn Arg ValVal Val Asp Pro 580 585 590 Val Val Thr Glu Gln Pro Ser Thr Ser Ser AlaAla Lys Thr Phe Ile 595 600 605 Thr Lys Ala Asn Ala Ser Ala Ile Pro GlyLys Thr Ile Leu Glu Asn 610 615 620 Ser Val Lys His Ser Lys Ala Leu AsnThr Leu Ser Ser Pro Gly Gln 625 630 635 640 Ser Ser Phe Ser His Gly ThrArg Asn Asn Ser Ala Lys Glu Asn Met 645 650 655 Glu Lys Glu Lys Pro ValLys Arg Lys Met Lys Ser Ser Val Leu Pro 660 665 670 Lys Ala Ser Thr LeuSer Lys Ser Ser Ala Val Ile Glu Gln Gly Asp 675 680 685 Cys Lys Asn AsnAla Leu Val Pro Gly Thr Ile Gln Val Asn Gly His 690 695 700 Gly Gly GlnPro Ser Lys Leu Val Lys Arg Gly Pro Gly Arg Lys Pro 705 710 715 720 LysVal Glu Val Asn Thr Asn Ser Gly Glu Ile Ile His Lys Lys Arg 725 730 735Gly Arg Lys Pro Lys Lys Leu Gln Tyr Ala Lys Pro Glu Asp Leu Glu 740 745750 Gln Asn Asn Val His Pro Ile Arg Asp Glu Val Leu Pro Ser Ser Thr 755760 765 Cys Asn Phe Leu Ser Glu Thr Asn Asn Val Lys Glu Asp Leu Leu Gln770 775 780 Lys Lys Asn Arg Gly Gly Arg Lys Pro Lys Arg Lys Met Lys ThrGln 785 790 795 800 Lys Leu Asp Ala Asp Leu Leu Val Pro Ala Ser Val LysVal Leu Arg 805 810 815 Arg Ser Asn Pro Lys Lys Ile Asp Asp Pro Ile AspGlu Glu Glu Glu 820 825 830 Phe Glu Glu Leu Lys Gly Ser Glu Pro His MetArg Thr Arg Asn Gln 835 840 845 Gly Arg Arg Thr Ala Phe Tyr Asn Glu AspAsp Ser Glu Glu Glu Gln 850 855 860 Arg Gln Leu Leu Phe Glu Asp Thr SerLeu Thr Phe Gly Thr Ser Ser 865 870 875 880 Arg Gly Arg Val Arg Lys LeuThr Glu Lys Ala Lys Ala Asn Leu Ile 885 890 895 Gly Trp 3 862 PRT Homosapiens 3 Met Gly Asp Glu Val Tyr Tyr Phe Arg Gln Gly His Glu Ala TyrVal 1 5 10 15 Glu Met Ala Arg Lys Asn Lys Ile Tyr Ser Ile Asn Pro LysLys Gln 20 25 30 Pro Trp His Lys Met Glu Leu Arg Glu Gln Glu Leu Met LysIle Val 35 40 45 Gly Ile Lys Tyr Glu Val Gly Leu Pro Thr Leu Cys Cys LeuLys Leu 50 55 60 Ala Phe Leu Asp Pro Asp Thr Gly Lys Leu Thr Gly Gly SerPhe Thr 65 70 75 80 Met Lys Tyr His Asp Met Pro Asp Val Ile Asp Phe LeuVal Leu Arg 85 90 95 Gln Gln Phe Asp Asp Ala Lys Tyr Arg Arg Trp Asn IleGly Asp Arg 100 105 110 Phe Arg Ser Val Ile Asp Asp Ala Trp Trp Phe GlyThr Ile Glu Ser 115 120 125 Gln Glu Pro Leu Gln Leu Glu Tyr Pro Asp SerLeu Phe Gln Cys Tyr 130 135 140 Asn Val Cys Trp Asp Asn Gly Asp Thr GluLys Met Ser Pro Trp Asp 145 150 155 160 Met Glu Leu Ile Pro Asn Asn AlaVal Phe Pro Glu Glu Leu Gly Thr 165 170 175 Ser Val Pro Leu Thr Asp GlyGlu Cys Arg Ser Leu Ile Tyr Lys Pro 180 185 190 Leu Asp Gly Glu Trp GlyThr Asn Pro Arg Asp Glu Glu Cys Glu Arg 195 200 205 Ile Val Ala Gly IleAsn Gln Leu Met Thr Leu Asp Ile Ala Ser Ala 210 215 220 Phe Val Ala ProVal Asp Leu Gln Ala Tyr Pro Met Tyr Cys Thr Val 225 230 235 240 Val AlaTyr Pro Thr Asp Leu Ser Thr Ile Lys Gln Arg Leu Glu Asn 245 250 255 ArgPhe Tyr Arg Arg Val Ser Ser Leu Met Trp Glu Val Arg Tyr Ile 260 265 270Glu His Asn Thr Arg Thr Phe Asn Glu Pro Gly Ser Pro Ile Val Lys 275 280285 Ser Ala Lys Phe Val Thr Asp Leu Leu Leu His Phe Ile Lys Asp Gln 290295 300 Thr Cys Tyr Asn Ile Ile Pro Leu Tyr Asn Ser Met Lys Lys Lys Val305 310 315 320 Leu Ser Asp Ser Glu Asp Glu Glu Lys Asp Val Asp Val ProGly Thr 325 330 335 Ser Thr Arg Lys Arg Lys Asp His Gln Arg Arg Arg ArgLeu Arg Asn 340 345 350 Arg Ala Gln Ser Tyr Asp Ile Gln Ala Trp Lys AsnGln Cys Glu Glu 355 360 365 Leu Leu Asn Leu Ile Phe Gln Cys Glu Asp SerGlu Pro Phe Arg Gln 370 375 380 Pro Val Asp Leu Leu Glu Tyr Pro Asp TyrArg Asp Ile Ile Asp Thr 385 390 395 400 Pro Met Asp Phe Ala Thr Val ArgGlu Thr Leu Glu Ala Gly Asn Tyr 405 410 415 Glu Ser Pro Met Glu Leu CysLys Asp Val Arg Leu Ile Phe Ser Asn 420 425 430 Ser Lys Ala Tyr Thr ProSer Lys Arg Ser Arg Ile Tyr Ser Met Ser 435 440 445 Leu Arg Leu Ser AlaPhe Phe Glu Glu His Ile Ser Ser Val Leu Ser 450 455 460 Asp Tyr Lys SerAla Leu Arg Phe His Lys Arg Asn Thr Ile Thr Lys 465 470 475 480 Arg ArgLys Lys Arg Asn Arg Ser Ser Ser Val Ser Ser Ser Ala Ala 485 490 495 SerSer Pro Glu Arg Lys Lys Arg Ile Leu Lys Pro Gln Leu Lys Ser 500 505 510Glu Ser Ser Thr Ser Ala Phe Ser Thr Pro Thr Arg Ser Ile Pro Pro 515 520525 Arg His Asn Ala Ala Gln Ile Asn Gly Lys Thr Glu Ser Ser Ser Val 530535 540 Val Arg Thr Arg Ser Asn Arg Val Val Val Asp Pro Val Val Thr Glu545 550 555 560 Gln Pro Ser Thr Ser Ser Ala Ala Lys Thr Phe Ile Thr LysAla Asn 565 570 575 Ala Ser Ala Ile Pro Gly Lys Thr Ile Leu Glu Asn SerVal Lys His 580 585 590 Ser Lys Ala Leu Asn Thr Leu Ser Ser Pro Gly GlnSer Ser Phe Ser 595 600 605 His Gly Thr Arg Asn Asn Ser Ala Lys Glu AsnMet Glu Lys Glu Lys 610 615 620 Pro Val Lys Arg Lys Met Lys Ser Ser ValLeu Pro Lys Ala Ser Thr 625 630 635 640 Leu Ser Lys Ser Ser Ala Val IleGlu Gln Gly Asp Cys Lys Asn Asn 645 650 655 Ala Leu Val Pro Gly Thr IleGln Val Asn Gly His Gly Gly Gln Pro 660 665 670 Ser Lys Leu Val Lys ArgGly Pro Gly Arg Lys Pro Lys Val Glu Val 675 680 685 Asn Thr Asn Ser GlyGlu Ile Ile His Lys Lys Arg Gly Arg Lys Pro 690 695 700 Lys Lys Leu GlnTyr Ala Lys Pro Glu Asp Leu Glu Gln Asn Asn Val 705 710 715 720 His ProIle Arg Asp Glu Val Leu Pro Ser Ser Thr Cys Asn Phe Leu 725 730 735 SerGlu Thr Asn Asn Val Lys Glu Asp Leu Leu Gln Lys Lys Asn Arg 740 745 750Gly Gly Arg Lys Pro Lys Arg Lys Met Lys Thr Gln Lys Leu Asp Ala 755 760765 Asp Leu Leu Val Pro Ala Ser Val Lys Val Leu Arg Arg Ser Asn Pro 770775 780 Lys Lys Ile Asp Asp Pro Ile Asp Glu Glu Glu Glu Phe Glu Glu Leu785 790 795 800 Lys Gly Ser Glu Pro His Met Arg Thr Arg Asn Gln Gly ArgArg Thr 805 810 815 Ala Phe Tyr Asn Glu Asp Asp Ser Glu Glu Glu Gln ArgGln Leu Leu 820 825 830 Phe Glu Asp Thr Ser Leu Thr Phe Gly Thr Ser SerArg Gly Arg Val 835 840 845 Arg Lys Leu Thr Glu Lys Ala Lys Ala Asn LeuIle Gly Trp 850 855 860 4 3841 DNA Mus musculus 4 ctagaagagt ttttagttttgtctgttagg atgtcttttg agagttttgt aaagaatata 60 cgttttgctt ttgtctctagccctccatca gtgattagga aaagctgaat aactttcgtc 120 acttctgctg cttttctagtaaaaggtttt aatactggag agtaaaattt ttgcacagat 180 ttatttcctt gtgtttgaagatagtactaa tgctgttgca tgctttctca gagattggct 240 gtaggagaac taactgagaatggcctaacg ttagaagagt ggttgccttc agcttggatt 300 acagacacac ttcccaggagatgtccattt gtgccacaga tgggtgatga ggtttattat 360 tttcgacaag ggcatgaagcatatgttgag atggcccgga aaaataaaat ttatagtatc 420 aatcctaaaa agcagccatggcataagatg gaactaaggg aacaagaact aatgaaaatt 480 gttggtataa agtatgaagtggggttgcct accctttgct gccttaaact tgcttttcta 540 gatcctgata ctggcaaactgaccggtgga tcatttacca tgaaatacca tgatatgcct 600 gacgtcatag attttctagtcttgagacaa caatttgatg atgcaaagta tagacgatgg 660 aatataggtg accgcttcagatctgtcata gatgatgcct ggtggtttgg aacaattgaa 720 agtcaagagc ctcttcaacctgagtaccct gatagtttgt ttcagtgtta taatgtatgt 780 tgggacaatg gagatacagaaaagatgagt ccttgggata tggaattaat acctaataat 840 gctgtctttc cagaagaactgggtaccagt gttcctttaa ctgatgttga atgtaggtcg 900 ctaatttata aacctcttgatggagattgg ggagccaatc ccagggatga agaatgtgaa 960 agaattgttg gaggaataaatcagctgatg acactagata ttgcgtctgc atttgttgcc 1020 cctgtggacc ttcaagcttatcccatgtat tgcactgtgg tggcctatcc aacggatcta 1080 agtacaatta aacaaagactggagaacagg ttttacaggc gcttttcatc actaatgtgg 1140 gaagttcgat atatagaacataatacacga acattcaatg agccaggaag cccaattgtg 1200 aaatctgcta aatttgtgactgatcttctc ctgcatttta taaaggatca gacttgttat 1260 aacataattc cactttacaactcaatgaag aagaaagttt tgtctgactc tgaggaagaa 1320 gagaaagatg ctgatgttccagggacttct accagaaagc gcaaggatca tcaacctaga 1380 agaaggttac gcaacagagctcagtcttac gatattcagg catggaagaa acaatgtcaa 1440 gaattactga atctcatatttcaatgtgaa gactcagaac cttttcgaca gccagtggat 1500 cttcttgaat atccagactaccgagacatc attgacactc caatggactt tgccactgtt 1560 agagagactt tagaggctgggaattatgag tcacccatgg agttatgtaa agatgtcagg 1620 ctcattttca gtaattctaaagcatacaca ccaagcaaga gatcaaggat ttacagcatg 1680 agtttacgcc tgtctgctttctttgaagaa catattagtt cagttttgtc agattataaa 1740 tctgctcttc gttttcataaaagaaacacc ataagcaaga agaggaagaa gcgaaacagg 1800 agcagctccc tgtccagcagtgctgcctca agccctgaaa ggaaaaaaag gatcttaaaa 1860 ccccagctaa agtcagaagtatctacctct ccattctcca tacctacaag atcagtacta 1920 ccaagacata atgctgcacaaatgaatggt aaaccagaat ccagttctgt ggttcgaact 1980 aggagcaacc gtgtagctgtagatccagtt gtcaccgagc agccctctac atcatcagcc 2040 acaaaagctt ttgtttcaaaaactaataca tctgccatgc caggaaaagc aatgctagag 2100 aattctgtga gacattccaaagccttgagc acactttcca gccctgatcc gctcacattc 2160 agccatgcta caaagaataattctgcaaaa gaaaacatgg aaaaggaaaa gcctgtcaaa 2220 cgtaaaatga agtcttctgtgttttcaaaa gcatctccac ttccaaagtc agccgcagtc 2280 atagagcaag gagagtgtaagaacaatgtt cttataccag gaaccattca agtaaatggc 2340 catggaggac aaccatcaaaactcgtgaag agaggacctg ggaggaagcc caaggtagaa 2400 gttaacacca gcagtggtgaagtgacacac aagaaaagag gtagaaagcc caagaatctg 2460 cagtgtgcaa agcaggaaaactctgagcaa aataacatgc atcccatcag ggctgacgtg 2520 cttccttctt caacatgcaacttcctttct gaaactaatg ctgtcaagga ggatttgtta 2580 cagaaaaaga gtcgtggaggcagaaaaccc aaaaggaaga tgaaaactca caacctagat 2640 tcagaactca tagttcctacaaatgttaaa gtgttaagga gaagtaaccg gaaaaaaaca 2700 gatgatccta tagatgaggaagaggagttt gaagaactca aaggctctga gcctcacatg 2760 agaactagaa atcagggtcgaaggacaact ttctataatg aggatgactc cgaggaagaa 2820 cagagacagc tgttgttcgaggacacctcc ttgacatttg gaacttctag tagaggacga 2880 gtccgaaagt tgactgaaaaagcaaaggct aatttaattg gttggtaact tgaagcaaaa 2940 tattgcattt taaaaaatctgtaacgcagg tacagttaag gagtaagtag aactaaggtc 3000 tctgcttcct tgctgctatgacggattagg gaatgttaca atttgacttg ggaaaatgga 3060 caaaaacaca tttagaagataatttacatc tttgaatgaa aaaaatctat atacatatat 3120 atttcaaatg tttgctatttattgccctta ggtaggttat tcggttccac attcatttca 3180 tttgctgttt gaaattgaggacctgttata aattctggtt tatttatgga agagacagct 3240 ctgctacact attaagaaacatagtattcc tagagataaa gtatgttccc tcttaaattg 3300 agttattttt gaccaagtgaggtacatttt tactgatagc agaaggcatg ccctaggaag 3360 agagatgtta caaagagtagcagtacatta agaatggctt cctctaaaga taactttcca 3420 gttcccacca tttggtatcctgaaaagtgt tgtgaactgt aggtgttcaa ttacagaata 3480 tctagaggaa gcttttgttttactccattt ctgccaaact taggagaaaa atgtattgat 3540 gcaaaggaaa catatccacattggaaaaca tttgactgtc taatttttca gaccttgatt 3600 cttatatcag tcactctatctctgtttatt gtgccaaaga ctgagaatca gtgcagtgga 3660 aagcctgttt ttgactgtcaggacagcata cacttttcag tactggaaaa gctatatatt 3720 ctaaagagca agttattacaaaattatgct gagttatatc ctttttttgg tactaaatgt 3780 aggaaaataa tgcactggtgggtcctttga cagagatatc ttagagaaaa aaaaaaaaaa 3840 g 3841 5 902 PRT Musmusculus 5 Met Leu Ser Gln Arg Leu Ala Val Gly Glu Leu Thr Glu Asn GlyLeu 1 5 10 15 Thr Leu Glu Glu Trp Leu Pro Ser Ala Trp Ile Thr Asp ThrLeu Pro 20 25 30 Arg Arg Cys Pro Phe Val Pro Gln Met Gly Asp Glu Val TyrTyr Phe 35 40 45 Arg Gln Gly His Glu Ala Tyr Val Glu Met Ala Arg Lys AsnLys Ile 50 55 60 Tyr Ser Ile Asn Pro Lys Lys Gln Pro Trp His Lys Met GluLeu Arg 65 70 75 80 Glu Gln Glu Leu Met Lys Ile Val Gly Ile Lys Tyr GluVal Gly Leu 85 90 95 Pro Thr Leu Cys Cys Leu Lys Leu Ala Phe Leu Asp ProAsp Thr Gly 100 105 110 Lys Leu Thr Gly Gly Ser Phe Thr Met Lys Tyr HisAsp Met Pro Asp 115 120 125 Val Ile Asp Phe Leu Val Leu Arg Gln Gln PheAsp Asp Ala Lys Tyr 130 135 140 Arg Arg Trp Asn Ile Gly Asp Arg Phe ArgSer Val Ile Asp Asp Ala 145 150 155 160 Trp Trp Phe Gly Thr Ile Glu SerGln Glu Pro Leu Gln Pro Glu Tyr 165 170 175 Pro Asp Ser Leu Phe Gln CysTyr Asn Val Cys Trp Asp Asn Gly Asp 180 185 190 Thr Glu Lys Met Ser ProTrp Asp Met Glu Leu Ile Pro Asn Asn Ala 195 200 205 Val Phe Pro Glu GluLeu Gly Thr Ser Val Pro Leu Thr Asp Val Glu 210 215 220 Cys Arg Ser LeuIle Tyr Lys Pro Leu Asp Gly Asp Trp Gly Ala Asn 225 230 235 240 Pro ArgAsp Glu Glu Cys Glu Arg Ile Val Gly Gly Ile Asn Gln Leu 245 250 255 MetThr Leu Asp Ile Ala Ser Ala Phe Val Ala Pro Val Asp Leu Gln 260 265 270Ala Tyr Pro Met Tyr Cys Thr Val Val Ala Tyr Pro Thr Asp Leu Ser 275 280285 Thr Ile Lys Gln Arg Leu Glu Asn Arg Phe Tyr Arg Arg Phe Ser Ser 290295 300 Leu Met Trp Glu Val Arg Tyr Ile Glu His Asn Thr Arg Thr Phe Asn305 310 315 320 Glu Pro Gly Ser Pro Ile Val Lys Ser Ala Lys Phe Val ThrAsp Leu 325 330 335 Leu Leu His Phe Ile Lys Asp Gln Thr Cys Tyr Asn IleIle Pro Leu 340 345 350 Tyr Asn Ser Met Lys Lys Lys Val Leu Ser Asp SerGlu Glu Glu Glu 355 360 365 Lys Asp Ala Asp Val Pro Gly Thr Ser Thr ArgLys Arg Lys Asp His 370 375 380 Gln Pro Arg Arg Arg Leu Arg Asn Arg AlaGln Ser Tyr Asp Ile Gln 385 390 395 400 Ala Trp Lys Lys Gln Cys Gln GluLeu Leu Asn Leu Ile Phe Gln Cys 405 410 415 Glu Asp Ser Glu Pro Phe ArgGln Pro Val Asp Leu Leu Glu Tyr Pro 420 425 430 Asp Tyr Arg Asp Ile IleAsp Thr Pro Met Asp Phe Ala Thr Val Arg 435 440 445 Glu Thr Leu Glu AlaGly Asn Tyr Glu Ser Pro Met Glu Leu Cys Lys 450 455 460 Asp Val Arg LeuIle Phe Ser Asn Ser Lys Ala Tyr Thr Pro Ser Lys 465 470 475 480 Arg SerArg Ile Tyr Ser Met Ser Leu Arg Leu Ser Ala Phe Phe Glu 485 490 495 GluHis Ile Ser Ser Val Leu Ser Asp Tyr Lys Ser Ala Leu Arg Phe 500 505 510His Lys Arg Asn Thr Ile Ser Lys Lys Arg Lys Lys Arg Asn Arg Ser 515 520525 Ser Ser Leu Ser Ser Ser Ala Ala Ser Ser Pro Glu Arg Lys Lys Arg 530535 540 Ile Leu Lys Pro Gln Leu Lys Ser Glu Val Ser Thr Ser Pro Phe Ser545 550 555 560 Ile Pro Thr Arg Ser Val Leu Pro Arg His Asn Ala Ala GlnMet Asn 565 570 575 Gly Lys Pro Glu Ser Ser Ser Val Val Arg Thr Arg SerAsn Arg Val 580 585 590 Ala Val Asp Pro Val Val Thr Glu Gln Pro Ser ThrSer Ser Ala Thr 595 600 605 Lys Ala Phe Val Ser Lys Thr Asn Thr Ser AlaMet Pro Gly Lys Ala 610 615 620 Met Leu Glu Asn Ser Val Arg His Ser LysAla Leu Ser Thr Leu Ser 625 630 635 640 Ser Pro Asp Pro Leu Thr Phe SerHis Ala Thr Lys Asn Asn Ser Ala 645 650 655 Lys Glu Asn Met Glu Lys GluLys Pro Val Lys Arg Lys Met Lys Ser 660 665 670 Ser Val Phe Ser Lys AlaSer Pro Leu Pro Lys Ser Ala Ala Val Ile 675 680 685 Glu Gln Gly Glu CysLys Asn Asn Val Leu Ile Pro Gly Thr Ile Gln 690 695 700 Val Asn Gly HisGly Gly Gln Pro Ser Lys Leu Val Lys Arg Gly Pro 705 710 715 720 Gly ArgLys Pro Lys Val Glu Val Asn Thr Ser Ser Gly Glu Val Thr 725 730 735 HisLys Lys Arg Gly Arg Lys Pro Lys Asn Leu Gln Cys Ala Lys Gln 740 745 750Glu Asn Ser Glu Gln Asn Asn Met His Pro Ile Arg Ala Asp Val Leu 755 760765 Pro Ser Ser Thr Cys Asn Phe Leu Ser Glu Thr Asn Ala Val Lys Glu 770775 780 Asp Leu Leu Gln Lys Lys Ser Arg Gly Gly Arg Lys Pro Lys Arg Lys785 790 795 800 Met Lys Thr His Asn Leu Asp Ser Glu Leu Ile Val Pro ThrAsn Val 805 810 815 Lys Val Leu Arg Arg Ser Asn Arg Lys Lys Thr Asp AspPro Ile Asp 820 825 830 Glu Glu Glu Glu Phe Glu Glu Leu Lys Gly Ser GluPro His Met Arg 835 840 845 Thr Arg Asn Gln Gly Arg Arg Thr Thr Phe TyrAsn Glu Asp Asp Ser 850 855 860 Glu Glu Glu Gln Arg Gln Leu Leu Phe GluAsp Thr Ser Leu Thr Phe 865 870 875 880 Gly Thr Ser Ser Arg Gly Arg ValArg Lys Leu Thr Glu Lys Ala Lys 885 890 895 Ala Asn Leu Ile Gly Trp 9006 862 PRT Mus musculus 6 Met Gly Asp Glu Val Tyr Tyr Phe Arg Gln Gly HisGlu Ala Tyr Val 1 5 10 15 Glu Met Ala Arg Lys Asn Lys Ile Tyr Ser IleAsn Pro Lys Lys Gln 20 25 30 Pro Trp His Lys Met Glu Leu Arg Glu Gln GluLeu Met Lys Ile Val 35 40 45 Gly Ile Lys Tyr Glu Val Gly Leu Pro Thr LeuCys Cys Leu Lys Leu 50 55 60 Ala Phe Leu Asp Pro Asp Thr Gly Lys Leu ThrGly Gly Ser Phe Thr 65 70 75 80 Met Lys Tyr His Asp Met Pro Asp Val IleAsp Phe Leu Val Leu Arg 85 90 95 Gln Gln Phe Asp Asp Ala Lys Tyr Arg ArgTrp Asn Ile Gly Asp Arg 100 105 110 Phe Arg Ser Val Ile Asp Asp Ala TrpTrp Phe Gly Thr Ile Glu Ser 115 120 125 Gln Glu Pro Leu Gln Pro Glu TyrPro Asp Ser Leu Phe Gln Cys Tyr 130 135 140 Asn Val Cys Trp Asp Asn GlyAsp Thr Glu Lys Met Ser Pro Trp Asp 145 150 155 160 Met Glu Leu Ile ProAsn Asn Ala Val Phe Pro Glu Glu Leu Gly Thr 165 170 175 Ser Val Pro LeuThr Asp Val Glu Cys Arg Ser Leu Ile Tyr Lys Pro 180 185 190 Leu Asp GlyAsp Trp Gly Ala Asn Pro Arg Asp Glu Glu Cys Glu Arg 195 200 205 Ile ValGly Gly Ile Asn Gln Leu Met Thr Leu Asp Ile Ala Ser Ala 210 215 220 PheVal Ala Pro Val Asp Leu Gln Ala Tyr Pro Met Tyr Cys Thr Val 225 230 235240 Val Ala Tyr Pro Thr Asp Leu Ser Thr Ile Lys Gln Arg Leu Glu Asn 245250 255 Arg Phe Tyr Arg Arg Phe Ser Ser Leu Met Trp Glu Val Arg Tyr Ile260 265 270 Glu His Asn Thr Arg Thr Phe Asn Glu Pro Gly Ser Pro Ile ValLys 275 280 285 Ser Ala Lys Phe Val Thr Asp Leu Leu Leu His Phe Ile LysAsp Gln 290 295 300 Thr Cys Tyr Asn Ile Ile Pro Leu Tyr Asn Ser Met LysLys Lys Val 305 310 315 320 Leu Ser Asp Ser Glu Glu Glu Glu Lys Asp AlaAsp Val Pro Gly Thr 325 330 335 Ser Thr Arg Lys Arg Lys Asp His Gln ProArg Arg Arg Leu Arg Asn 340 345 350 Arg Ala Gln Ser Tyr Asp Ile Gln AlaTrp Lys Lys Gln Cys Gln Glu 355 360 365 Leu Leu Asn Leu Ile Phe Gln CysGlu Asp Ser Glu Pro Phe Arg Gln 370 375 380 Pro Val Asp Leu Leu Glu TyrPro Asp Tyr Arg Asp Ile Ile Asp Thr 385 390 395 400 Pro Met Asp Phe AlaThr Val Arg Glu Thr Leu Glu Ala Gly Asn Tyr 405 410 415 Glu Ser Pro MetGlu Leu Cys Lys Asp Val Arg Leu Ile Phe Ser Asn 420 425 430 Ser Lys AlaTyr Thr Pro Ser Lys Arg Ser Arg Ile Tyr Ser Met Ser 435 440 445 Leu ArgLeu Ser Ala Phe Phe Glu Glu His Ile Ser Ser Val Leu Ser 450 455 460 AspTyr Lys Ser Ala Leu Arg Phe His Lys Arg Asn Thr Ile Ser Lys 465 470 475480 Lys Arg Lys Lys Arg Asn Arg Ser Ser Ser Leu Ser Ser Ser Ala Ala 485490 495 Ser Ser Pro Glu Arg Lys Lys Arg Ile Leu Lys Pro Gln Leu Lys Ser500 505 510 Glu Val Ser Thr Ser Pro Phe Ser Ile Pro Thr Arg Ser Val LeuPro 515 520 525 Arg His Asn Ala Ala Gln Met Asn Gly Lys Pro Glu Ser SerSer Val 530 535 540 Val Arg Thr Arg Ser Asn Arg Val Ala Val Asp Pro ValVal Thr Glu 545 550 555 560 Gln Pro Ser Thr Ser Ser Ala Thr Lys Ala PheVal Ser Lys Thr Asn 565 570 575 Thr Ser Ala Met Pro Gly Lys Ala Met LeuGlu Asn Ser Val Arg His 580 585 590 Ser Lys Ala Leu Ser Thr Leu Ser SerPro Asp Pro Leu Thr Phe Ser 595 600 605 His Ala Thr Lys Asn Asn Ser AlaLys Glu Asn Met Glu Lys Glu Lys 610 615 620 Pro Val Lys Arg Lys Met LysSer Ser Val Phe Ser Lys Ala Ser Pro 625 630 635 640 Leu Pro Lys Ser AlaAla Val Ile Glu Gln Gly Glu Cys Lys Asn Asn 645 650 655 Val Leu Ile ProGly Thr Ile Gln Val Asn Gly His Gly Gly Gln Pro 660 665 670 Ser Lys LeuVal Lys Arg Gly Pro Gly Arg Lys Pro Lys Val Glu Val 675 680 685 Asn ThrSer Ser Gly Glu Val Thr His Lys Lys Arg Gly Arg Lys Pro 690 695 700 LysAsn Leu Gln Cys Ala Lys Gln Glu Asn Ser Glu Gln Asn Asn Met 705 710 715720 His Pro Ile Arg Ala Asp Val Leu Pro Ser Ser Thr Cys Asn Phe Leu 725730 735 Ser Glu Thr Asn Ala Val Lys Glu Asp Leu Leu Gln Lys Lys Ser Arg740 745 750 Gly Gly Arg Lys Pro Lys Arg Lys Met Lys Thr His Asn Leu AspSer 755 760 765 Glu Leu Ile Val Pro Thr Asn Val Lys Val Leu Arg Arg SerAsn Arg 770 775 780 Lys Lys Thr Asp Asp Pro Ile Asp Glu Glu Glu Glu PheGlu Glu Leu 785 790 795 800 Lys Gly Ser Glu Pro His Met Arg Thr Arg AsnGln Gly Arg Arg Thr 805 810 815 Thr Phe Tyr Asn Glu Asp Asp Ser Glu GluGlu Gln Arg Gln Leu Leu 820 825 830 Phe Glu Asp Thr Ser Leu Thr Phe GlyThr Ser Ser Arg Gly Arg Val 835 840 845 Arg Lys Leu Thr Glu Lys Ala LysAla Asn Leu Ile Gly Trp 850 855 860 7 3263 DNA Homo sapiens 7 cggatcttggagaatccaaa aagcaacaga caaatcaaca caattatcgt acaagatctg 60 cattggaagagactcctaga ccctcagaag agatagaaaa tggcagtagt tcttcagatg 120 aaggcgaagtagttgctgtc agtggtggaa catccgaaga agaagagaga gcatggcaca 180 gtgatggcagttctagtgac tactccagtg attactctga ctggacagca gatgcaggaa 240 ttaatctgcagccaccaaag aaagttccta agaataaaac caagaaagca gaaagcagtt 300 cagatgaagaagaagaatct gaaaaacaga agcaaaaaca gattaaaaag ggaaaagaaa 360 aagcaaatgaagaaaaagat ggaccaatat caccaaagaa aaagaagccc aaagaaagaa 420 aacaaaagagattggctgtg ggagaactaa ctgaaaatgg tttgacatta gaagaatggt 480 tgccatcaacatggattaca gataccattc cccgaagatg tccatttgtg ccacagatgg 540 gtgatgaggtttattatttc cgacaaggac atgaagccta tgtcgaaatg gcccggaaaa 600 ataaaatatatagtatcaat cccaaaaaac aaccatggca taaaatggag ctacgggaac 660 aagaacttatgaaaatagtt ggcataaagt atgaagtggg attacctacc ctttgctgcc 720 ttaaacttgcttttctagat cctgatactg gtaaactgac tggtggatca tttaccatga 780 aataccatgatatgcctgac gtcatagatt ttctagtctt gagacaacaa tttgatgatg 840 caaaatacaggcgatggaat ataggtgacc gcttcaggtc tgtcatagat gatgcctggt 900 ggtttggaacaatcgaaagc caggaacctc ttcaacttga gtaccctgat agtctgtttc 960 aatgctacaatgtttgctgg gacaatggag atacagaaaa gatgagtcct tgggatatgg 1020 agcttatacctaataatgct gtatttcctg aagaactagg taccagtgtt cctttaactg 1080 atggtgagtgcagatcacta atctataaac ctcttgatgg agaatggggt accaatccca 1140 gggatgaagaatgtgaaaga attgtggcag gaataaacca gttgatgaca ctagatattg 1200 cctcagcatttgtggccccc gtggatctgc aagcctatcc catgtattgc acagtagtgg 1260 catatccaacggatctaagt acaattaaac aaagactgga aaacaggttt tacaggcggg 1320 tttcttccctaatgtgggaa gttcgatata tagagcataa tacacgaaca tttaatgagc 1380 ctggaagccctattgtgaaa tctgctaaat tcgtgactga tcttcttcta cattttataa 1440 aggatcagacttgttataac ataattccac tttataattc aatgaagaag aaagttttgt 1500 ctgattctgaggatgaagag aaagatgttg atgtgccagg aacttctact cgaaaaagga 1560 aggaccatcagcgtagaaga agattacgta atagagccca gtcttacgat attcaagcat 1620 ggaagaaccagtgtgaagaa ttgttaaatc tcatatttca atgtgaagat tcagagcctt 1680 tccgtcagccggtagatctc cttgaatatc cagactacag agacatcatt gacactccaa 1740 tggattttgctaccgttaga gaaactttag aggctgggaa ttatgagtca ccaatggagt 1800 tatgtaaagatgtcagactt attttcagta attccaaagc atatacacca agcaaaagat 1860 caaggatttacagcatgagt ttgcgcctgt ctgctttctt tgaagaacac attagttcag 1920 ttttatcagattataaatct gctcttcgtt ttcataaaag aaataccata accaaaagga 1980 ggaagaaaagaaacagaagc agctctgttt ccagtagtgc tgcatcaagc cctgaaagga 2040 aaaaaaggatcttaaaaccc cagctaaaat cagaaagctc tacctctgca ttctctacac 2100 ctacacgatcaataccgcca agacacaatg ctgctcagat aaacggtaaa acagaatcta 2160 gttctgtggttcgaaccaga agcaaccgag tggttgtaga tccagttgtc actgagcaac 2220 catctacttcttcagctgca aagactttta ttacaaaagc taatgcatct gcaataccag 2280 ggaaaacaatactagagaat tctgtgaaac attccaaagc tttgaatact ctttccagtc 2340 ctggtcaatccagttttagt catggcacta ggaataattc tgcaaaagaa aacatggaaa 2400 aggaaaagccagtcaaacgt aaaatgaagt catctgtact cccaaaggcg tccactcttt 2460 caaagtcatcagctgtcatt gagcaaggag attgtaagaa caacgctctt gtaccaggaa 2520 ccattcaagtaaatggccat ggaggacagc catcaaaact tgtgaagagg ggacctggaa 2580 ggaaacctaaagtagaagtt aataccaata gtggtgaaat tatacacaag aaaaggggta 2640 gaaagcccaaaaagctacag tatgcaaagc cagaagattt agagcaaaat aatgtgcatc 2700 ccatcagagatgaagtactt ccttcttcaa catgcaattt tctttctgaa actaataatg 2760 taaaggaagatttgttacag aaaaagaatc gtggaggtag gaagcccaaa aggaagatga 2820 agacacaaaaattagatgca gatctcctag tccctgcaag tgtcaaagtg ttaaggagaa 2880 gtaacccgaaaaaaatagat gatcctatag atgaggaaga agagtttgaa gaactcaaag 2940 gctctgaaccccacatgaga actagaaatc aaggtcgaag gacagctttc tataatgagg 3000 atgactctgaagaggagcaa aggcagctgt tgttcgaaga cacctcttta acttttggaa 3060 cttctagtagaggacgagtc cgaaagttga ctgaaaaagc aaaagctaat ttaattggtt 3120 ggtaacttgtaccaaaatat tttacttcaa aatctataaa gcaggtacag ttaaggaata 3180 agtaggactaaggcttctgc ttccttgctg ctgtggtgga gtagggaatg ttatgatttg 3240 atttgcaaaaaaaaaaaaaa aag 3263 8 1041 PRT Homo sapiens 8 Leu Asp Leu Gly Glu SerLys Lys Gln Gln Thr Asn Gln His Asn Tyr 1 5 10 15 Arg Thr Arg Ser AlaLeu Glu Glu Thr Pro Arg Pro Ser Glu Glu Ile 20 25 30 Glu Asn Gly Ser SerSer Ser Asp Glu Gly Glu Val Val Ala Val Ser 35 40 45 Gly Gly Thr Ser GluGlu Glu Glu Arg Ala Trp His Ser Asp Gly Ser 50 55 60 Ser Ser Asp Tyr SerSer Asp Tyr Ser Asp Trp Thr Ala Asp Ala Gly 65 70 75 80 Ile Asn Leu GlnPro Pro Lys Lys Val Pro Lys Asn Lys Thr Lys Lys 85 90 95 Ala Glu Ser SerSer Asp Glu Glu Glu Glu Ser Glu Lys Gln Lys Gln 100 105 110 Lys Gln IleLys Lys Glu Lys Lys Lys Val Asn Glu Glu Lys Asp Gly 115 120 125 Pro IleSer Pro Lys Lys Lys Lys Pro Lys Glu Arg Lys Gln Lys Arg 130 135 140 LeuAla Val Gly Glu Leu Thr Glu Asn Gly Leu Thr Leu Glu Glu Trp 145 150 155160 Leu Pro Ser Thr Trp Ile Thr Asp Thr Ile Pro Arg Arg Cys Pro Phe 165170 175 Val Pro Gln Met Gly Asp Glu Val Tyr Tyr Phe Arg Gln Gly His Glu180 185 190 Ala Tyr Val Glu Met Ala Arg Lys Asn Lys Ile Tyr Ser Ile AsnPro 195 200 205 Lys Lys Gln Pro Trp His Lys Met Glu Leu Arg Glu Gln GluLeu Met 210 215 220 Lys Ile Val Gly Ile Lys Tyr Glu Val Gly Leu Pro ThrLeu Cys Cys 225 230 235 240 Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr GlyLys Leu Thr Gly Gly 245 250 255 Ser Phe Thr Met Lys Tyr His Asp Met ProAsp Val Ile Asp Phe Leu 260 265 270 Val Leu Arg Gln Gln Phe Asp Asp AlaLys Tyr Arg Arg Trp Asn Ile 275 280 285 Gly Asp Arg Phe Arg Ser Val IleAsp Asp Ala Trp Trp Phe Gly Thr 290 295 300 Ile Glu Ser Gln Glu Pro LeuGln Leu Glu Tyr Pro Asp Ser Leu Phe 305 310 315 320 Gln Cys Tyr Asn ValCys Trp Asp Asn Gly Asp Thr Glu Lys Met Ser 325 330 335 Pro Trp Asp MetGlu Leu Ile Pro Asn Asn Ala Val Phe Pro Glu Glu 340 345 350 Leu Gly ThrSer Val Pro Leu Thr Asp Gly Glu Cys Arg Ser Leu Ile 355 360 365 Tyr LysPro Leu Asp Gly Glu Trp Gly Thr Asn Pro Arg Asp Glu Glu 370 375 380 CysGlu Arg Ile Val Ala Gly Ile Asn Gln Leu Met Thr Leu Asp Ile 385 390 395400 Ala Ser Ala Phe Val Ala Pro Val Asp Leu Gln Ala Tyr Pro Met Tyr 405410 415 Cys Thr Val Val Ala Tyr Pro Thr Asp Leu Ser Thr Ile Lys Gln Arg420 425 430 Leu Glu Asn Arg Phe Tyr Arg Arg Val Ser Ser Leu Met Trp GluVal 435 440 445 Arg Tyr Ile Glu His Asn Thr Arg Thr Phe Asn Glu Pro GlySer Pro 450 455 460 Ile Val Lys Ser Ala Lys Phe Val Thr Asp Leu Leu LeuHis Phe Ile 465 470 475 480 Lys Asp Gln Thr Cys Tyr Asn Ile Ile Pro LeuTyr Asn Ser Met Lys 485 490 495 Lys Lys Val Leu Ser Asp Ser Glu Asp GluGlu Lys Asp Val Asp Val 500 505 510 Pro Gly Thr Ser Thr Arg Lys Arg LysAsp His Gln Arg Arg Arg Arg 515 520 525 Leu Arg Asn Arg Ala Gln Ser TyrAsp Ile Gln Ala Trp Lys Asn Gln 530 535 540 Cys Glu Glu Leu Leu Asn LeuIle Phe Gln Cys Glu Asp Ser Glu Pro 545 550 555 560 Phe Arg Gln Pro ValAsp Leu Leu Glu Tyr Pro Asp Tyr Arg Asp Ile 565 570 575 Ile Asp Thr ProMet Asp Phe Ala Thr Val Arg Glu Thr Leu Glu Ala 580 585 590 Gly Asn TyrGlu Ser Pro Met Glu Leu Cys Lys Asp Val Arg Leu Ile 595 600 605 Phe SerAsn Ser Lys Ala Tyr Thr Pro Ser Lys Arg Ser Arg Ile Tyr 610 615 620 SerMet Ser Leu Arg Leu Ser Ala Phe Phe Glu Glu His Ile Ser Ser 625 630 635640 Val Leu Ser Asp Tyr Lys Ser Ala Leu Arg Phe His Lys Arg Asn Thr 645650 655 Ile Thr Lys Arg Arg Lys Lys Arg Asn Arg Ser Ser Ser Val Ser Ser660 665 670 Ser Ala Ala Ser Ser Pro Glu Arg Lys Lys Arg Ile Leu Lys ProGln 675 680 685 Leu Lys Ser Glu Ser Ser Thr Ser Ala Phe Ser Thr Pro ThrArg Ser 690 695 700 Ile Pro Pro Arg His Asn Ala Ala Gln Ile Asn Gly LysThr Glu Ser 705 710 715 720 Ser Ser Val Val Arg Thr Arg Ser Asn Arg ValVal Val Asp Pro Val 725 730 735 Val Thr Glu Gln Pro Ser Thr Ser Ser AlaAla Lys Thr Phe Ile Thr 740 745 750 Lys Ala Asn Ala Ser Ala Ile Pro GlyLys Thr Ile Leu Glu Asn Ser 755 760 765 Val Lys His Ser Lys Ala Leu AsnThr Leu Ser Ser Pro Gly Gln Ser 770 775 780 Ser Phe Ser His Gly Thr ArgAsn Asn Ser Ala Lys Glu Asn Met Glu 785 790 795 800 Lys Glu Lys Pro ValLys Arg Lys Met Lys Ser Ser Val Leu Pro Lys 805 810 815 Ala Ser Thr LeuSer Lys Ser Ser Ala Val Ile Glu Gln Gly Asp Cys 820 825 830 Lys Asn AsnAla Leu Val Pro Gly Thr Ile Gln Val Asn Gly His Gly 835 840 845 Gly GlnPro Ser Lys Leu Val Lys Arg Gly Pro Gly Arg Lys Pro Lys 850 855 860 ValGlu Val Asn Thr Asn Ser Gly Glu Ile Ile His Lys Lys Arg Gly 865 870 875880 Arg Lys Pro Lys Lys Leu Gln Tyr Ala Lys Pro Glu Asp Leu Glu Gln 885890 895 Asn Asn Val His Pro Ile Arg Asp Glu Val Leu Pro Ser Ser Thr Cys900 905 910 Asn Phe Leu Ser Glu Thr Asn Asn Val Lys Glu Asp Leu Leu GlnLys 915 920 925 Lys Asn Arg Gly Gly Arg Lys Pro Lys Arg Lys Met Lys ThrGln Lys 930 935 940 Leu Asp Ala Asp Leu Leu Val Pro Ala Ser Val Lys ValLeu Arg Arg 945 950 955 960 Ser Asn Pro Lys Lys Ile Asp Asp Pro Ile AspGlu Glu Glu Glu Phe 965 970 975 Glu Glu Leu Lys Gly Ser Glu Pro His MetArg Thr Arg Asn Gln Gly 980 985 990 Arg Arg Thr Ala Phe Tyr Asn Glu AspAsp Ser Glu Glu Glu Gln Arg 995 1000 1005 Gln Leu Leu Phe Glu Asp ThrSer Leu Thr Phe Gly Thr Ser Ser 1010 1015 1020 Arg Gly Arg Val Arg LysLeu Thr Glu Lys Ala Lys Ala Asn Leu 1025 1030 1035 Ile Gly Trp 1040 93819 DNA Mus musculus 9 ggacagcaga tgctggaatt aacttgcagc caccaaagcccgttcctcct aagcataaaa 60 ccaagaaacc agaaagtagt tcagatgaag aagaagaatctgaaaaccag aagcaaaaac 120 atattaaaaa ggaaagaaaa aaagcaaatg aagaaaaagatggaccaaca tcaccaaaga 180 aaaaaaagcc caaagaaaga aaacaaaaga gattggctgtaggagaacta actgagaatg 240 gcctaacgtt agaagagtgg ttgccttcag cttggattacagacacactt cccaggagat 300 gtccatttgt gccacagatg ggtgatgagg tttattattttcgacaaggg catgaagcat 360 atgttgagat ggcccggaaa aataaaattt atagtatcaatcctaaaaag cagccatggc 420 ataagatgga actaagggaa caagaactaa tgaaaattgttggtataaag tatgaagtgg 480 ggttgcctac cctttgctgc cttaaacttg cttttctagatcctgatact ggcaaactga 540 ccggtggatc atttaccatg aaataccatg atatgcctgacgtcatagat tttctagtct 600 tgagacaaca atttgatgat gcaaagtata gacgatggaatataggtgac cgcttcagat 660 ctgtcataga tgatgcctgg tggtttggaa caattgaaagtcaagagcct cttcaacctg 720 agtaccctga tagtttgttt cagtgttata atgtatgttgggacaatgga gatacagaaa 780 agatgagtcc ttgggatatg gaattaatac ctaataatgctgtctttcca gaagaactgg 840 gtaccagtgt tcctttaact gatgttgaat gtaggtcgctaatttataaa cctcttgatg 900 gagattgggg agccaatccc agggatgaag aatgtgaaagaattgttgga ggaataaatc 960 agctgatgac actagatatt gcgtctgcat ttgttgcccctgtggacctt caagcttatc 1020 ccatgtattg cactgtggtg gcctatccaa cggatctaagtacaattaaa caaagactgg 1080 agaacaggtt ttacaggcgc ttttcatcac taatgtgggaagttcgatat atagaacata 1140 atacacgaac attcaatgag ccaggaagcc caattgtgaaatctgctaaa tttgtgactg 1200 atcttctcct gcattttata aaggatcaga cttgttataacataattcca ctttacaact 1260 caatgaagaa gaaagttttg tctgactctg aggaagaagagaaagatgct gatgttccag 1320 ggacttctac cagaaagcgc aaggatcatc aacctagaagaaggttacgc aacagagctc 1380 agtcttacga tattcaggca tggaagaaac aatgtcaagaattactgaat ctcatatttc 1440 aatgtgaaga ctcagaacct tttcgacagc cagtggatcttcttgaatat ccagactacc 1500 gagacatcat tgacactcca atggactttg ccactgttagagagacttta gaggctggga 1560 attatgagtc acccatggag ttatgtaaag atgtcaggctcattttcagt aattctaaag 1620 catacacacc aagcaagaga tcaaggattt acagcatgagtttacgcctg tctgctttct 1680 ttgaagaaca tattagttca gttttgtcag attataaatctgctcttcgt tttcataaaa 1740 gaaacaccat aagcaagaag aggaagaagc gaaacaggagcagctccctg tccagcagtg 1800 ctgcctcaag ccctgaaagg aaaaaaagga tcttaaaaccccagctaaag tcagaagtat 1860 ctacctctcc attctccata cctacaagat cagtactaccaagacataat gctgcacaaa 1920 tgaatggtaa accagaatcc agttctgtgg ttcgaactaggagcaaccgt gtagctgtag 1980 atccagttgt caccgagcag ccctctacat catcagccacaaaagctttt gtttcaaaaa 2040 ctaatacatc tgccatgcca ggaaaagcaa tgctagagaattctgtgaga cattccaaag 2100 ccttgagcac actttccagc cctgatccgc tcacattcagccatgctaca aagaataatt 2160 ctgcaaaaga aaacatggaa aaggaaaagc ctgtcaaacgtaaaatgaag tcttctgtgt 2220 tttcaaaagc atctccactt ccaaagtcag ccgcagtcatagagcaagga gagtgtaaga 2280 acaatgttct tataccagga accattcaag taaatggccatggaggacaa ccatcaaaac 2340 tcgtgaagag aggacctggg aggaagccca aggtagaagttaacaccagc agtggtgaag 2400 tgacacacaa gaaaagaggt agaaagccca agaatctgcagtgtgcaaag caggaaaact 2460 ctgagcaaaa taacatgcat cccatcaggg ctgacgtgcttccttcttca acatgcaact 2520 tcctttctga aactaatgct gtcaaggagg atttgttacagaaaaagagt cgtggaggca 2580 gaaaacccaa aaggaagatg aaaactcaca acctagattcagaactcata gttcctacaa 2640 atgttaaagt gttaaggaga agtaaccgga aaaaaacagatgatcctata gatgaggaag 2700 aggagtttga agaactcaaa ggctctgagc ctcacatgagaactagaaat cagggtcgaa 2760 ggacaacttt ctataatgag gatgactccg aggaagaacagagacagctg ttgttcgagg 2820 acacctcctt gacatttgga acttctagta gaggacgagtccgaaagttg actgaaaaag 2880 caaaggctaa tttaattggt tggtaacttg aagcaaaatattgcatttta aaaaatctgt 2940 aacgcaggta cagttaagga gtaagtagaa ctaaggtctctgcttccttg ctgctatgac 3000 ggattaggga atgttacaat ttgacttggg aaaatggacaaaaacacatt tagaagataa 3060 tttacatctt tgaatgaaaa aaatctatat acatatatatttcaaatgtt tgctatttat 3120 tgcccttagg taggttattc ggttccacat tcatttcatttgctgtttga aattgaggac 3180 ctgttataaa ttctggttta tttatggaag agacagctctgctacactat taagaaacat 3240 agtattccta gagataaagt atgttccctc ttaaattgagttatttttga ccaagtgagg 3300 tacattttta ctgatagcag aaggcatgcc ctaggaagagagatgttaca aagagtagca 3360 gtacattaag aatggcttcc tctaaagata actttccagttcccaccatt tggtatcctg 3420 aaaagtgttg tgaactgtag gtgttcaatt acagaatatctagaggaagc ttttgtttta 3480 ctccatttct gccaaactta ggagaaaaat gtattgatgcaaaggaaaca tatccacatt 3540 ggaaaacatt tgactgtcta atttttcaga ccttgattcttatatcagtc actctatctc 3600 tgtttattgt gccaaagact gagaatcagt gcagtggaaagcctgttttt gactgtcagg 3660 acagcataca cttttcagta ctggaaaagc tatatattctaaagagcaag ttattacaaa 3720 attatgctga gttatatcct ttttttggta ctaaatgtaggaaaataatg cactggtggg 3780 tcctttgaca gagatatctt agagaaaaaa aaaaaaaag3819 10 967 PRT Mus musculus 10 Trp Thr Ala Asp Ala Gly Ile Asn Leu GlnPro Pro Lys Lys Val Pro 1 5 10 15 Lys His Lys Thr Lys Lys Pro Glu SerSer Ser Asp Glu Glu Glu Glu 20 25 30 Ser Glu Asn Gln Lys Gln Lys His IleLys Lys Glu Arg Lys Lys Ala 35 40 45 Asn Glu Glu Lys Asp Gly Pro Thr SerPro Lys Lys Lys Lys Pro Lys 50 55 60 Glu Arg Lys Gln Lys Arg Leu Ala ValGly Glu Leu Thr Glu Asn Gly 65 70 75 80 Leu Thr Leu Glu Glu Trp Leu ProSer Ala Trp Ile Thr Asp Thr Leu 85 90 95 Pro Arg Arg Cys Pro Phe Val ProGln Met Gly Asp Glu Val Tyr Tyr 100 105 110 Phe Arg Gln Gly His Glu AlaTyr Val Glu Met Ala Arg Lys Asn Lys 115 120 125 Ile Tyr Ser Ile Asn ProLys Lys Gln Pro Trp His Lys Met Glu Leu 130 135 140 Arg Glu Gln Glu LeuMet Lys Ile Val Gly Ile Lys Tyr Glu Val Gly 145 150 155 160 Leu Pro ThrLeu Cys Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr 165 170 175 Gly LysLeu Thr Gly Gly Ser Phe Thr Met Lys Tyr His Asp Met Pro 180 185 190 AspVal Ile Asp Phe Leu Val Leu Arg Gln Gln Phe Asp Asp Ala Lys 195 200 205Tyr Arg Arg Trp Asn Ile Gly Asp Arg Phe Arg Ser Val Ile Asp Asp 210 215220 Ala Trp Trp Phe Gly Thr Ile Glu Ser Gln Glu Pro Leu Gln Pro Glu 225230 235 240 Tyr Pro Asp Ser Leu Phe Gln Cys Tyr Asn Val Cys Trp Asp AsnGly 245 250 255 Asp Thr Glu Lys Met Ser Pro Trp Asp Met Glu Leu Ile ProAsn Asn 260 265 270 Ala Val Phe Pro Glu Glu Leu Gly Thr Ser Val Pro LeuThr Asp Val 275 280 285 Glu Cys Arg Ser Leu Ile Tyr Lys Pro Leu Asp GlyAsp Trp Gly Ala 290 295 300 Asn Pro Arg Asp Glu Glu Cys Glu Arg Ile ValGly Gly Ile Asn Gln 305 310 315 320 Leu Met Thr Leu Asp Ile Ala Ser AlaPhe Val Ala Pro Val Asp Leu 325 330 335 Gln Ala Tyr Pro Met Tyr Cys ThrVal Val Ala Tyr Pro Thr Asp Leu 340 345 350 Ser Thr Ile Lys Gln Arg LeuGlu Asn Arg Phe Tyr Arg Arg Phe Ser 355 360 365 Ser Leu Met Trp Glu ValArg Tyr Ile Glu His Asn Thr Arg Thr Phe 370 375 380 Asn Glu Pro Gly SerPro Ile Val Lys Ser Ala Lys Phe Val Thr Asp 385 390 395 400 Leu Leu LeuHis Phe Ile Lys Asp Gln Thr Cys Tyr Asn Ile Ile Pro 405 410 415 Leu TyrAsn Ser Met Lys Lys Lys Val Leu Ser Asp Ser Glu Glu Glu 420 425 430 GluLys Asp Ala Asp Val Pro Gly Thr Ser Thr Arg Lys Arg Lys Asp 435 440 445His Gln Pro Arg Arg Arg Leu Arg Asn Arg Ala Gln Ser Tyr Asp Ile 450 455460 Gln Ala Trp Lys Lys Gln Cys Gln Glu Leu Leu Asn Leu Ile Phe Gln 465470 475 480 Cys Glu Asp Ser Glu Pro Phe Arg Gln Pro Val Asp Leu Leu GluTyr 485 490 495 Pro Asp Tyr Arg Asp Ile Ile Asp Thr Pro Met Asp Phe AlaThr Val 500 505 510 Arg Glu Thr Leu Glu Ala Gly Asn Tyr Glu Ser Pro MetGlu Leu Cys 515 520 525 Lys Asp Val Arg Leu Ile Phe Ser Asn Ser Lys AlaTyr Thr Pro Ser 530 535 540 Lys Arg Ser Arg Ile Tyr Ser Met Ser Leu ArgLeu Ser Ala Phe Phe 545 550 555 560 Glu Glu His Ile Ser Ser Val Leu SerAsp Tyr Lys Ser Ala Leu Arg 565 570 575 Phe His Lys Arg Asn Thr Ile SerLys Lys Arg Lys Lys Arg Asn Arg 580 585 590 Ser Ser Ser Leu Ser Ser SerAla Ala Ser Ser Pro Glu Arg Lys Lys 595 600 605 Arg Ile Leu Lys Pro GlnLeu Lys Ser Glu Val Ser Thr Ser Pro Phe 610 615 620 Ser Ile Pro Thr ArgSer Val Leu Pro Arg His Asn Ala Ala Gln Met 625 630 635 640 Asn Gly LysPro Glu Ser Ser Ser Val Val Arg Thr Arg Ser Asn Arg 645 650 655 Val AlaVal Asp Pro Val Val Thr Glu Gln Pro Ser Thr Ser Ser Ala 660 665 670 ThrLys Ala Phe Val Ser Lys Thr Asn Thr Ser Ala Met Pro Gly Lys 675 680 685Ala Met Leu Glu Asn Ser Val Arg His Ser Lys Ala Leu Ser Thr Leu 690 695700 Ser Ser Pro Asp Pro Leu Thr Phe Ser His Ala Thr Lys Asn Asn Ser 705710 715 720 Ala Lys Glu Asn Met Glu Lys Glu Lys Pro Val Lys Arg Lys MetLys 725 730 735 Ser Ser Val Phe Ser Lys Ala Ser Pro Leu Pro Lys Ser AlaAla Val 740 745 750 Ile Glu Gln Gly Glu Cys Lys Asn Asn Val Leu Ile ProGly Thr Ile 755 760 765 Gln Val Asn Gly His Gly Gly Gln Pro Ser Lys LeuVal Lys Arg Gly 770 775 780 Pro Gly Arg Lys Pro Lys Val Glu Val Asn ThrSer Ser Gly Glu Val 785 790 795 800 Thr His Lys Lys Arg Gly Arg Lys ProLys Asn Leu Gln Cys Ala Lys 805 810 815 Gln Glu Asn Ser Glu Gln Asn AsnMet His Pro Ile Arg Ala Asp Val 820 825 830 Leu Pro Ser Ser Thr Cys AsnPhe Leu Ser Glu Thr Asn Ala Val Lys 835 840 845 Glu Asp Leu Leu Gln LysLys Ser Arg Gly Gly Arg Lys Pro Lys Arg 850 855 860 Lys Met Lys Thr HisAsn Leu Asp Ser Glu Leu Ile Val Pro Thr Asn 865 870 875 880 Val Lys ValLeu Arg Arg Ser Asn Arg Lys Lys Thr Asp Asp Pro Ile 885 890 895 Asp GluGlu Glu Glu Phe Glu Glu Leu Lys Gly Ser Glu Pro His Met 900 905 910 ArgThr Arg Asn Gln Gly Arg Arg Thr Thr Phe Tyr Asn Glu Asp Asp 915 920 925Ser Glu Glu Glu Gln Arg Gln Leu Leu Phe Glu Asp Thr Ser Leu Thr 930 935940 Phe Gly Thr Ser Ser Arg Gly Arg Val Arg Lys Leu Thr Glu Lys Ala 945950 955 960 Lys Ala Asn Leu Ile Gly Trp 965 11 615 DNA Homo sapiens 11agattggctg tgggagaact aactgaaaat ggtttgacat tagaagaatg gttgccatca 60acatggatta cagataccat tccccgaaga tgtccatttg tgccacagat gggtgatgag 120gtttattatt tccgacaagg acatgaagcc tatgtcgaaa tggcccggaa aaataaaata 180tatagtatca atcccaaaaa acaaccatgg cataaaatgg agctacggga acaagaactt 240atgaaaatag ttggcataaa gtatgaagtg ggattaccta ccctttgctg ccttaaactt 300gcttttctag atcctgatac tggtaaactg actggtggat catttaccat gaaataccat 360gatatgcctg acgtcataga ttttctagtc ttgagacaac aatttgatga tgcaaaatac 420aggcgatgga atataggtga ccgcttcagg tctgtcatag atgatgcctg gtggtttgga 480acaatcgaaa gccaggaacc tcttcaactt gagtaccctg atagtctgtt tcaatgctac 540aatgtttgct gggacaatgg agatacagaa aagatgagtc cttgggatat ggagcttata 600cctaataatg ctgta 615 12 205 PRT Homo sapiens 12 Arg Leu Ala Val Gly GluLeu Thr Glu Asn Gly Leu Thr Leu Glu Glu 1 5 10 15 Trp Leu Pro Ser ThrTrp Ile Thr Asp Thr Ile Pro Arg Arg Cys Pro 20 25 30 Phe Val Pro Gln MetGly Asp Glu Val Tyr Tyr Phe Arg Gln Gly His 35 40 45 Glu Ala Tyr Val GluMet Ala Arg Lys Asn Lys Ile Tyr Ser Ile Asn 50 55 60 Pro Lys Lys Gln ProTrp His Lys Met Glu Leu Arg Glu Gln Glu Leu 65 70 75 80 Met Lys Ile ValGly Ile Lys Tyr Glu Val Gly Leu Pro Thr Leu Cys 85 90 95 Cys Leu Lys LeuAla Phe Leu Asp Pro Asp Thr Gly Lys Leu Thr Gly 100 105 110 Gly Ser PheThr Met Lys Tyr His Asp Met Pro Asp Val Ile Asp Phe 115 120 125 Leu ValLeu Arg Gln Gln Phe Asp Asp Ala Lys Tyr Arg Arg Trp Asn 130 135 140 IleGly Asp Arg Phe Arg Ser Val Ile Asp Asp Ala Trp Trp Phe Gly 145 150 155160 Thr Ile Glu Ser Gln Glu Pro Leu Gln Leu Glu Tyr Pro Asp Ser Leu 165170 175 Phe Gln Cys Tyr Asn Val Cys Trp Asp Asn Gly Asp Thr Glu Lys Met180 185 190 Ser Pro Trp Asp Met Glu Leu Ile Pro Asn Asn Ala Val 195 200205 13 205 PRT Mus musculus 13 Arg Leu Ala Val Gly Glu Leu Thr Glu AsnGly Leu Thr Leu Glu Glu 1 5 10 15 Trp Leu Pro Ser Ala Trp Ile Thr AspThr Leu Pro Arg Arg Cys Pro 20 25 30 Phe Val Pro Gln Met Gly Asp Glu ValTyr Tyr Phe Arg Gln Gly His 35 40 45 Glu Ala Tyr Val Glu Met Ala Arg LysAsn Lys Ile Tyr Ser Ile Asn 50 55 60 Pro Lys Lys Gln Pro Trp His Lys MetGlu Leu Arg Glu Gln Glu Leu 65 70 75 80 Met Lys Ile Val Gly Ile Lys TyrGlu Val Gly Leu Pro Thr Leu Cys 85 90 95 Cys Leu Lys Leu Ala Phe Leu AspPro Asp Thr Gly Lys Leu Thr Gly 100 105 110 Gly Ser Phe Thr Met Lys TyrHis Asp Met Pro Asp Val Ile Asp Phe 115 120 125 Leu Val Leu Arg Gln GlnPhe Asp Asp Ala Lys Tyr Arg Arg Trp Asn 130 135 140 Ile Gly Asp Arg PheArg Ser Val Ile Asp Asp Ala Trp Trp Phe Gly 145 150 155 160 Thr Ile GluSer Gln Glu Pro Leu Gln Pro Glu Tyr Pro Asp Ser Leu 165 170 175 Phe GlnCys Tyr Asn Val Cys Trp Asp Asn Gly Asp Thr Glu Lys Met 180 185 190 SerPro Trp Asp Met Glu Leu Ile Pro Asn Asn Ala Val 195 200 205 14 345 DNAHomo sapiens 14 aaacctcttg atggagaatg gggtaccaat cccagggatg aagaatgtgaaagaattgtg 60 gcaggaataa accagttgat gacactagat attgcctcag catttgtggcccccgtggat 120 ctgcaagcct atcccatgta ttgcacagta gtggcatatc caacggatctaagtacaatt 180 aaacaaagac tggaaaacag gttttacagg cgggtttctt ccctaatgtgggaagttcga 240 tatatagagc ataatacacg aacatttaat gagcctggaa gccctattgtgaaatctgct 300 aaattcgtga ctgatcttct tctacatttt ataaaggatc agact 345 15115 PRT Homo sapiens 15 Lys Pro Leu Asp Gly Glu Trp Gly Thr Asn Pro ArgAsp Glu Glu Cys 1 5 10 15 Glu Arg Ile Val Ala Gly Ile Asn Gln Leu MetThr Leu Asp Ile Ala 20 25 30 Ser Ala Phe Val Ala Pro Val Asp Leu Gln AlaTyr Pro Met Tyr Cys 35 40 45 Thr Val Val Ala Tyr Pro Thr Asp Leu Ser ThrIle Lys Gln Arg Leu 50 55 60 Glu Asn Arg Phe Tyr Arg Arg Val Ser Ser LeuMet Trp Glu Val Arg 65 70 75 80 Tyr Ile Glu His Asn Thr Arg Thr Phe AsnGlu Pro Gly Ser Pro Ile 85 90 95 Val Lys Ser Ala Lys Phe Val Thr Asp LeuLeu Leu His Phe Ile Lys 100 105 110 Asp Gln Thr 115 16 351 DNA Homosapiens 16 agaagaagat tacgtaatag agcccagtct tacgatattc aagcatggaagaaccagtgt 60 gaagaattgt taaatctcat atttcaatgt gaagattcag agcctttccgtcagccggta 120 gatctccttg aatatccaga ctacagagac atcattgaca ctccaatggattttgctacc 180 gttagagaaa ctttagaggc tgggaattat gagtcaccaa tggagttatgtaaagatgtc 240 agacttattt tcagtaattc caaagcatat acaccaagca aaagatcaaggatttacagc 300 atgagtttgc gcctgtctgc tttctttgaa gaacacatta gttcagtttt a351 17 117 PRT Homo sapiens 17 Arg Arg Arg Leu Arg Asn Arg Ala Gln SerTyr Asp Ile Gln Ala Trp 1 5 10 15 Lys Asn Gln Cys Glu Glu Leu Leu AsnLeu Ile Phe Gln Cys Glu Asp 20 25 30 Ser Glu Pro Phe Arg Gln Pro Val AspLeu Leu Glu Tyr Pro Asp Tyr 35 40 45 Arg Asp Ile Ile Asp Thr Pro Met AspPhe Ala Thr Val Arg Glu Thr 50 55 60 Leu Glu Ala Gly Asn Tyr Glu Ser ProMet Glu Leu Cys Lys Asp Val 65 70 75 80 Arg Leu Ile Phe Ser Asn Ser LysAla Tyr Thr Pro Ser Lys Arg Ser 85 90 95 Arg Ile Tyr Ser Met Ser Leu ArgLeu Ser Ala Phe Phe Glu Glu His 100 105 110 Ile Ser Ser Val Leu 115 18120 DNA Homo sapiens 18 agattggctg tgggagaact aactgaaaat ggtttgacattagaagaatg gttgccatca 60 acatggatta cagataccat tccccgaaga tgtccatttgtgccacagat gggtgatgag 120 19 108 DNA Homo sapiens 19 gtttattatttccgacaagg acatgaagcc tatgtcgaaa tggcccggaa aaataaaata 60 tatagtatcaatcccaaaaa acaaccatgg cataaaatgg agctacgg 108 20 125 DNA Homo sapiens 20gaacaagaac ttatgaaaat agttggcata aagtatgaag tgggattacc taccctttgc 60tgccttaaac ttgcttttct agatcctgat actggtaaac tgactggtgg atcatttacc 120atgaa 125 21 83 DNA Homo sapiens 21 ataccatgat atgcctgacg tcatagattttctagtcttg agacaacaat ttgatgatgc 60 aaaatacagg cgatggaata tag 83 22 112DNA Homo sapiens 22 gtgaccgctt caggtctgtc atagatgatg cctggtggtttggaacaatc gaaagccagg 60 aacctcttca acttgagtac cctgatagtc tgtttcaatgctacaatgtt tg 112 23 62 DNA Homo sapiens 23 ctgggacaat ggagatacagaaaagatgag tccttgggat atggagctta tacctaataa 60 tg 62 24 156 DNA Homosapiens 24 ctgtatttcc tgaagaacta ggtaccagtg ttcctttaac tgatggtgagtgcagatcac 60 taatctataa acctcttgat ggagaatggg gtaccaatcc cagggatgaagaatgtgaaa 120 gaattgtggc aggaataaac cagttgatga cactag 156 25 121 DNAHomo sapiens 25 atattgcctc agcatttgtg gcccccgtgg atctgcaagc ctatcccatgtattgcacag 60 tagtggcata tccaacggat ctaagtacaa ttaaacaaag actggaaaacaggttttaca 120 g 121 26 126 DNA Homo sapiens 26 gcgggtttct tccctaatgtgggaagttcg atatatagag cataatacac gaacatttaa 60 tgagcctgga agccctattgtgaaatctgc taaattcgtg actgatcttc ttctacattt 120 tataaa 126 27 70 DNAHomo sapiens 27 ggatcagact tgttataaca taattccact ttataattca atgaagaagaaagttttgtc 60 tgattctgag 70 28 51 DNA Homo sapiens 28 gatgaagagaaagatgttga tgtgccagga acttctactc gaaaaaggaa g 51 29 150 DNA Homo sapiens29 gaccatcagc gtagaagaag attacgtaat agagcccagt cttacgatat tcaagcatgg 60aagaaccagt gtgaagaatt gttaaatctc atatttcaat gtgaagattc agagcctttc 120cgtcagccgg tagatctcct tgaatatcca 150 30 153 DNA Homo sapiens 30gactacagag acatcattga cactccaatg gattttgcta ccgttagaga aactttagag 60gctgggaatt atgagtcacc aatggagtta tgtaaagatg tcagacttat tttcagtaat 120tccaaagcat atacaccaag caaaagatca agg 153 31 164 DNA Homo sapiens 31atttacagca tgagtttgcg cctgtctgct ttctttgaag aacacattag ttcagtttta 60tcagattata aatctgctct tcgttttcat aaaagaaata ccataaccaa aaggaggaag 120aaaagaaaca gaagcagctc tgtttccagt agtgctgcat caag 164 32 260 DNA Homosapiens 32 ccctgaaagg aaaaaaagga tcttaaaacc ccagctaaaa tcagaaagctctacctctgc 60 attctctaca cctacacgat caataccgcc aagacacaat gctgctcagataaacggtaa 120 aacagaatct agttctgtgg ttcgaaccag aagcaaccga gtggttgtagatccagttgt 180 cactgagcaa ccatctactt cttcagctgc aaagactttt attacaaaagctaatgcatc 240 tgcaatacca gggaaaacaa 260 33 198 DNA Homo sapiens 33tactagagaa ttctgtgaaa cattccaaag ctttgaatac tctttccagt cctggtcaat 60ccagttttag tcatggcact aggaataatt ctgcaaaaga aaacatggaa aaggaaaagc 120cagtcaaacg taaaatgaag tcatctgtac tcccaaaggc gtccactctt tcaaagtcat 180cagctgtcat tgagcaag 198 34 776 DNA Homo sapiens 34 gagattgtaa gaacaacgctcttgtaccag gaaccattca agtaaatggc catggaggac 60 agccatcaaa acttgtgaagaggggacctg gaaggaaacc taaagtagaa gttaatacca 120 atagtggtga aattatacacaagaaaaggg gtagaaagcc caaaaagcta cagtatgcaa 180 agccagaaga tttagagcaaaataatgtgc atcccatcag agatgaagta cttccttctt 240 caacatgcaa ttttctttctgaaactaata atgtaaagga agatttgtta cagaaaaaga 300 atcgtggagg taggaagcccaaaaggaaga tgaagacaca aaaattagat gcagatctcc 360 tagtccctgc aagtgtcaaagtgttaagga gaagtaaccc gaaaaaaata gatgatccta 420 tagatgagga agaagagtttgaagaactca aaggctctga accccacatg agaactagaa 480 atcaaggtcg aaggacagctttctataatg aggatgactc tgaagaggag caaaggcagc 540 tgttgttcga agacacctctttaacttttg gaacttctag tagaggacga gtccgaaagt 600 tgactgaaaa agcaaaagctaatttaattg gttggtaact tgtaccaaaa tattttactt 660 caaaatctat aaagcaggtacagttaagga ataagtagga ctaaggcttc tgcttccttg 720 ctgctgtggt ggagtagggaatgttatgat ttgatttgca aaaaaaaaaa aaaaag 776 35 3123 DNA Homo sapiens 35ccgaagctcg gctcgtgaac acacactgac agctataggg caggcggcgg caccgtcccc 60gcttcccctc ggcggcgggg tgtcccgtcg gcggccctga agtgacccat aaacatgtct 120tgtgagagga aaggcctctc ggagctgcga tcggagctct acttcctcat cgcccggttc 180ctggaagatg gaccctgtca gcaggcggct caggtgctga tccgcgaggt ggccgagaag 240gagctgctgc cccggcgcac cgactggacc gggaaggagc atcccaggac ctaccagaat 300ctggtgaagt attacagaca cttagcacct gatcacttgc tgcaaatatg tcatcgacta 360ggacctcttc ttgaacaaga aattcctcaa agtgttcctg gagtacaaac tttattagga 420gctggaagac agtctttact acgcacaaat aaaagctgca agcatgttgt gtggaaagga 480tctgctctgg ctgcgttgca ctgtggaaga ccacctgagt caccagttaa ctatggtagc 540ccacccagca ttgcggatac tctgttttca aggaagctga atgggaaata cagacttgag 600cgacttgttc caactgcagt gtatcagcac atgaaaatgc ataaacgaat tcttggacac 660ttgtcatctg tgtactgtgt aacttttgat cgaactggca gacggatatt tactggttct 720gatgactgtc ttgtgaaaat atgggcaaca gatgatggga ggttgttagc taccttaaga 780ggacatgctg ctgaaatatc agacatggct gtaaactatg agaataccat gatagcagct 840ggaagttgtg ataaaatgat ccgagtctgg tgtcttcgaa cctgtgcacc tttggctgtt 900cttcagggcc atagtgcatc tattacatca ctacagttct caccattgtg cagtggctca 960aagagatatc tatcttctac tggggcagat ggcactattt gtttttggct ctgggatgct 1020ggaaccctta aaataaaccc aagacctgca aaatttacag agcgccctcg gcctggagtt 1080caaatgatct gttcttcttt tagtgctggt ggaatgtttc tggcgacggg aagcacagat 1140catattattc gggtttattt ttttggatca ggtcagccag agaaaatatc agaattggag 1200tttcatactg acaaagttga cagtatccag ttttccaaca ctagtaacag gtttgtaagt 1260ggcagtcgtg atgggacagc acgtatttgg caatttaaac gaagagagtg gaagagcatt 1320ttgttggata tggctactcg tccagcaggc caaaaccttc aaggaataga agataaaatc 1380acaaaaatga aggttactat ggtagcttgg gatcgacatg acaatacagt tataactgca 1440gttaataaca tgactctgaa agtttggaat tcttacactg gtcaactaat tcatgtcctg 1500atgggtcatg aagatgaggt atttgttctt gaaccacacc cgttcgatcc tagagttctc 1560ttttctgctg gtcatgatgg aaacgtgata gtgtgggatc tggcaagagg agtcaaaata 1620cgatcttatt tcaatatgat tgaaggccaa ggacatggcg cagtatttga ctgcaaatgc 1680tctcctgatg gtcagcattt tgcatgcaca gactctcatg gacatctttt aatttttggc 1740tttgggtcca gtagcaaata tgacaagata gcagatcaga tgttctttca tagtgattat 1800cggccactta ttcgtgatgc caacaatttt gtattagatg aacagactca gcaagcacct 1860catcttatgc ctcccccttt tttggttgat gttgatggta accctcatcc atcaagatat 1920caaagattag ttcctggccg tgaaaattgc agggaggagc aactcatccc tcagatggga 1980gtaacttcct caggactgaa tcaagtttta agtcagcaag caaaccagga gatcagccca 2040ctggacagca tgattcaaag actacaacag gagcaagacc tgagacgttc tggtgaagca 2100gttatcagta ataccagccg tttaagtaga ggctccataa gttctacctc agaggttcat 2160tcaccaccaa acgtaggact aagacgtagt ggacaaattg aaggtgtacg gcaaatgcac 2220agcaacgcac caagaagtga aatagccaca gagcgggatc tggtagcttg gagtcgaagg 2280gtggtagtac ccgagctatc agctggtgta gccagtaggc aagaagaatg gagaactgca 2340aagggagaag aagaaataaa gacttacagg tcagaagaga aaagaaaaca cttaactgtt 2400ccaaaagaga ataaaatacc cactgtctca aagaatcatg ctcatgagca tttcctggat 2460cttggagaat ccaaaaagca acagacaaat caacacaatt atcgtacaag atctgcattg 2520gaagagactc ctagaccctc agaagagata gaaaatggca gtagttcttc agatgaaggc 2580gaagtagttg ctgtcagtgg tggaacatcc gaagaagaag agagagcatg gcacagtgat 2640ggcagttcta gtgactactc cagtgattac tctgactgga cagcagatgc aggaattaat 2700ctgcagccac caaagaaagt tcctaagaat aaaaccaaga aagcagaaag cagttcagat 2760gaagaagaag aatctgaaaa acagaagcaa aaacagatta aaaaggaaaa gaaaaaagta 2820aatgaagaaa aagatggacc aatatcacca aagaaaaaga agcccaaaga aagaaaacaa 2880aagagattgg ctgtgggaga actaactgaa aatggtttga cattagaaga atggttgcca 2940tcaacatgga ttacagatac cattccccga agatgtccat ttgtgccaca gatgggtgat 3000gaggtttatt atttccgaca aggacatgaa gcctatgtcg aaatggcccg gaaaaataaa 3060atatatagta tcaatcccaa aaaacaacca tggcataaaa tggagctacg ggtatgacat 3120tga 3123 36 1000 PRT Homo sapiens 36 Met Ser Cys Glu Arg Lys Gly Leu SerGlu Leu Arg Ser Glu Leu Tyr 1 5 10 15 Phe Leu Ile Ala Arg Phe Leu GluAsp Gly Pro Cys Gln Gln Ala Ala 20 25 30 Gln Val Leu Ile Arg Glu Val AlaGlu Lys Glu Leu Leu Pro Arg Arg 35 40 45 Thr Asp Trp Thr Gly Lys Glu HisPro Arg Thr Tyr Gln Asn Leu Val 50 55 60 Lys Tyr Tyr Arg His Leu Ala ProAsp His Leu Leu Gln Ile Cys His 65 70 75 80 Arg Leu Gly Pro Leu Leu GluGln Glu Ile Pro Gln Ser Val Pro Gly 85 90 95 Val Gln Thr Leu Leu Gly AlaGly Arg Gln Ser Leu Leu Arg Thr Asn 100 105 110 Lys Ser Cys Lys His ValVal Trp Lys Gly Ser Ala Leu Ala Ala Leu 115 120 125 His Cys Gly Arg ProPro Glu Ser Pro Val Asn Tyr Gly Ser Pro Pro 130 135 140 Ser Ile Ala AspThr Leu Phe Ser Arg Lys Leu Asn Gly Lys Tyr Arg 145 150 155 160 Leu GluArg Leu Val Pro Thr Ala Val Tyr Gln His Met Lys Met His 165 170 175 LysArg Ile Leu Gly His Leu Ser Ser Val Tyr Cys Val Thr Phe Asp 180 185 190Arg Thr Gly Arg Arg Ile Phe Thr Gly Ser Asp Asp Cys Leu Val Lys 195 200205 Ile Trp Ala Thr Asp Asp Gly Arg Leu Leu Ala Thr Leu Arg Gly His 210215 220 Ala Ala Glu Ile Ser Asp Met Ala Val Asn Tyr Glu Asn Thr Met Ile225 230 235 240 Ala Ala Gly Ser Cys Asp Lys Met Ile Arg Val Trp Cys LeuArg Thr 245 250 255 Cys Ala Pro Leu Ala Val Leu Gln Gly His Ser Ala SerIle Thr Ser 260 265 270 Leu Gln Phe Ser Pro Leu Cys Ser Gly Ser Lys ArgTyr Leu Ser Ser 275 280 285 Thr Gly Ala Asp Gly Thr Ile Cys Phe Trp LeuTrp Asp Ala Gly Thr 290 295 300 Leu Lys Ile Asn Pro Arg Pro Ala Lys PheThr Glu Arg Pro Arg Pro 305 310 315 320 Gly Val Gln Met Ile Cys Ser SerPhe Ser Ala Gly Gly Met Phe Leu 325 330 335 Ala Thr Gly Ser Thr Asp HisIle Ile Arg Val Tyr Phe Phe Gly Ser 340 345 350 Gly Gln Pro Glu Lys IleSer Glu Leu Glu Phe His Thr Asp Lys Val 355 360 365 Asp Ser Ile Gln PheSer Asn Thr Ser Asn Arg Phe Val Ser Gly Ser 370 375 380 Arg Asp Gly ThrAla Arg Ile Trp Gln Phe Lys Arg Arg Glu Trp Lys 385 390 395 400 Ser IleLeu Leu Asp Met Ala Thr Arg Pro Ala Gly Gln Asn Leu Gln 405 410 415 GlyIle Glu Asp Lys Ile Thr Lys Met Lys Val Thr Met Val Ala Trp 420 425 430Asp Arg His Asp Asn Thr Val Ile Thr Ala Val Asn Asn Met Thr Leu 435 440445 Lys Val Trp Asn Ser Tyr Thr Gly Gln Leu Ile His Val Leu Met Gly 450455 460 His Glu Asp Glu Val Phe Val Leu Glu Pro His Pro Phe Asp Pro Arg465 470 475 480 Val Leu Phe Ser Ala Gly His Asp Gly Asn Val Ile Val TrpAsp Leu 485 490 495 Ala Arg Gly Val Lys Ile Arg Ser Tyr Phe Asn Met IleGlu Gly Gln 500 505 510 Gly His Gly Ala Val Phe Asp Cys Lys Cys Ser ProAsp Gly Gln His 515 520 525 Phe Ala Cys Thr Asp Ser His Gly His Leu LeuIle Phe Gly Phe Gly 530 535 540 Ser Ser Ser Lys Tyr Asp Lys Ile Ala AspGln Met Phe Phe His Ser 545 550 555 560 Asp Tyr Arg Pro Leu Ile Arg AspAla Asn Asn Phe Val Leu Asp Glu 565 570 575 Gln Thr Gln Gln Ala Pro HisLeu Met Pro Pro Pro Phe Leu Val Asp 580 585 590 Val Asp Gly Asn Pro HisPro Ser Arg Tyr Gln Arg Leu Val Pro Gly 595 600 605 Arg Glu Asn Cys ArgGlu Glu Gln Leu Ile Pro Gln Met Gly Val Thr 610 615 620 Ser Ser Gly LeuAsn Gln Val Leu Ser Gln Gln Ala Asn Gln Glu Ile 625 630 635 640 Ser ProLeu Asp Ser Met Ile Gln Arg Leu Gln Gln Glu Gln Asp Leu 645 650 655 ArgArg Ser Gly Glu Ala Val Ile Ser Asn Thr Ser Arg Leu Ser Arg 660 665 670Gly Ser Ile Ser Ser Thr Ser Glu Val His Ser Pro Pro Asn Val Gly 675 680685 Leu Arg Arg Ser Gly Gln Ile Glu Gly Val Arg Gln Met His Ser Asn 690695 700 Ala Pro Arg Ser Glu Ile Ala Thr Glu Arg Asp Leu Val Ala Trp Ser705 710 715 720 Arg Arg Val Val Val Pro Glu Leu Ser Ala Gly Val Ala SerArg Gln 725 730 735 Glu Glu Trp Arg Thr Ala Lys Gly Glu Glu Glu Ile LysThr Tyr Arg 740 745 750 Ser Glu Glu Lys Arg Lys His Leu Thr Val Pro LysGlu Asn Lys Ile 755 760 765 Pro Thr Val Ser Lys Asn His Ala His Glu HisPhe Leu Asp Leu Gly 770 775 780 Glu Ser Lys Lys Gln Gln Thr Asn Gln HisAsn Tyr Arg Thr Arg Ser 785 790 795 800 Ala Leu Glu Glu Thr Pro Arg ProSer Glu Glu Ile Glu Asn Gly Ser 805 810 815 Ser Ser Ser Asp Glu Gly GluVal Val Ala Val Ser Gly Gly Thr Ser 820 825 830 Glu Glu Glu Glu Arg AlaTrp His Ser Asp Gly Ser Ser Ser Asp Tyr 835 840 845 Ser Ser Asp Tyr SerAsp Trp Thr Ala Asp Ala Gly Ile Asn Leu Gln 850 855 860 Pro Pro Lys LysVal Pro Lys Asn Lys Thr Lys Lys Ala Glu Ser Ser 865 870 875 880 Ser AspGlu Glu Glu Glu Ser Glu Lys Gln Lys Gln Lys Gln Ile Lys 885 890 895 LysGlu Lys Lys Lys Val Asn Glu Glu Lys Asp Gly Pro Ile Ser Pro 900 905 910Lys Lys Lys Lys Pro Lys Glu Arg Lys Gln Lys Arg Leu Ala Val Gly 915 920925 Glu Leu Thr Glu Asn Gly Leu Thr Leu Glu Glu Trp Leu Pro Ser Thr 930935 940 Trp Ile Thr Asp Thr Ile Pro Arg Arg Cys Pro Phe Val Pro Gln Met945 950 955 960 Gly Asp Glu Val Tyr Tyr Phe Arg Gln Gly His Glu Ala TyrVal Glu 965 970 975 Met Ala Arg Lys Asn Lys Ile Tyr Ser Ile Asn Pro LysLys Gln Pro 980 985 990 Trp His Lys Met Glu Leu Arg Val 995 1000 37 3316DNA Mus musculus 37 gagccgaggc tcggctcgtg agcacacact gacagctacagggcaggcgg cggcaccgtc 60 cccgcgtccc ctcggcggcg gggtgtcccg ccggcggccccgaagtgacc cgcaaacatg 120 tctcgtgaga ggaaaggcct ctcggagctg cgatcggagctctacttcct catcgcccgg 180 ttcctggaag atggaccctg tcagcaggcg gctcaggtgctgatccgcga agtggccgag 240 aaggagctgc tgccccggcg caccgactgg accgggaaggagcaccccag gacctaccag 300 aatctggtga agtattatag acaccttgca cctgatcacttgctgcaaat atgtcatcgg 360 ctaggacctc ttcttgagca agaaattcct cagagtgttcctggagtaca gactttacta 420 ggagctggaa gacagtcctt gctacgaaca aataaaagctgcaagcatgt ggtatggaaa 480 ggatctgccc tggctgcact gcactgtggg aggccgccagagtctccagt taactacggt 540 agcccaccta gcattgcgga tactctgttt tcaaggaagctgaatgggaa atacagactt 600 gaacgacttg ttccaactgc agtttatcag cacatgaagatgcataagcg aattcttgga 660 cacttatcat cggtgtactg tgtaactttt gatcgaactggcaggcggat atttactggt 720 tctgatgatt gtcttgtgaa aatctgggcc acagacgatggaagattgct agctacttta 780 agaggacatg ctgctgaaat atcagacatg gctgtaaactatgagaatac tatgatagca 840 gctggaagtt gtgataaaat gattcgtgtc tggtgtcttcgaacctgtgc acctttggct 900 gttcttcagg gacatagtgc atctattaca tcactacagttctcaccatt gtgcagtggc 960 tcaaagagat acctgtcttc tacaggggcg gacggcactatttgcttttg gctttgggat 1020 gctggaaccc ttaaaataaa tccaagaccc acaaaatttacagagcgtcc tcggcctgga 1080 gtgcaaatga tatgttcttc gttcagtgct ggtgggatgtttttggccac tggaagcact 1140 gaccatatta ttagagttta tttttttgga tcaggtcagccagaaaaaat atcagaattg 1200 gagtttcata ctgacaaagt tgacagtatc cagttttccaacactagtaa caggtttgtg 1260 agtggtagtc gtgatgggac agcacgaatt tggcagtttaaacgaaggga atggaaaagc 1320 attttgttag atatggctac tcgtccagca ggccaaaatcttcaaggcat agaagacaaa 1380 atcacaaaaa tgaaagtaac tatggtagct tgggatcgacatgacaacac agttataact 1440 gcagttaata acatgactct gaaagtttgg aattcttatactggtcaact gatacatgtt 1500 ctaatgggtc atgaagatga ggtgtttgtt cttgagccacacccatttga tcctagagtt 1560 ctcttctctg ctggtcatga tggaaatgtg atagtgtgggatctagcaag aggagtcaaa 1620 gttcgatctt atttcaatat gattgaagga caaggacatggtgcagtgtt tgactgcaaa 1680 tgctcccctg atggtcagca ctttgcatgt acagactctcatggacatct tttaattttt 1740 ggttttgggt ccagtagcaa gtatgacaag atagcagatcagatgttttt tcacagtgat 1800 tatcggcctc ttatccgtga tgcgaacaat tttgtattagatgagcagac gcagcaggca 1860 cctcacctca tgcctccccc ttttctggtt gatgttgatggaaatcctca tccatcaagg 1920 taccagcgat tggttcctgg tcgggagaac tgcagggaggagcagctcat tcctcagatg 1980 ggagtaactt cttcaggatt gaaccaagtt ttgagccagcaagcaaacca ggatattagt 2040 cctttagaca gcatgattca aagactgcag caggagcaggacctgaggcg ttcgggtgaa 2100 gcaggtgtta gtaatgccag ccgtgtgaac agaggctcagtaagttctac ctccgaagtt 2160 cattcaccac caaatatagg attaaggcgc agtggccaaatcgaaggtgt acggcagatg 2220 cacagcaatg ctccgagaag tgaaatagcc acagagcgagatcttgttgc ttggagtcgg 2280 agggtagtag tgcctgagct ctcggctggt gtggctagtagacaagaaga atggagaact 2340 gcaaagggag aagaggaaat aaagagttat agatcagaagagaaaaggaa acacttaact 2400 gttgcaaaag agaataaaat acttactgtc tcaaagaatcatgctcatga gcatttcctg 2460 gatcttgggg attctaaaaa gcagcaagcg aatcagcacaattaccgtac aagatctgca 2520 ctggaagaaa cacccaggcc cttagaggag ctagaaaacggaactagttc ttcagatgaa 2580 ggtgaagtac ttgctgtcag tggtgggact tctgaggaagaggagcgagc atggcacagt 2640 gatggcagct ccagtgacta ctccagtgat tattctgattggacagcaga tgctggaatt 2700 aacttgcagc caccaaagaa agttcctaag cataaaaccaagaaaccaga aagtagttca 2760 gatgaagaag aagaatctga aaaccagaag caaaaacatattaaaaagga aagaaaaaaa 2820 gcaaatgaag aaaaagatgg accaacatca ccaaagaaaaaaaagcccaa agaaagaaaa 2880 caaaagagat tggctgtagg agaactaact gagaatggcctaacgttaga agagtggttg 2940 ccttcagctt ggattacaga cacacttccc aggagatgtccatttgtgcc acagatgggt 3000 gatgaggttt attattttcg acaagggcat gaagcatatgttgaaatggc ccggaaaaat 3060 aaaatttata gtatcaatcc taaaaagcag ccatggcataagatggaact aagggtaaat 3120 attggcatat tttttaatgt aaaatatatt ttttgcattattagagaagt tgtgtgaagg 3180 tttactcttt gactgtaaga aactggggct ggggaataagagttcagaag gtaatatgct 3240 tccatgaaag tgtaaagatt gccgggcagt ggtggcgcacacctttagtc ccagcacttg 3300 ggaggcagag gcaggc 3316 38 1066 PRT Musmusculus 38 Met Ser Arg Glu Arg Lys Gly Leu Ser Glu Leu Arg Ser Glu LeuTyr 1 5 10 15 Phe Leu Ile Ala Arg Phe Leu Glu Asp Gly Pro Cys Gln GlnAla Ala 20 25 30 Gln Val Leu Ile Arg Glu Val Ala Glu Lys Glu Leu Leu ProArg Arg 35 40 45 Thr Asp Trp Thr Gly Lys Glu His Pro Arg Thr Tyr Gln AsnLeu Val 50 55 60 Lys Tyr Tyr Arg His Leu Ala Pro Asp His Leu Leu Gln IleCys His 65 70 75 80 Arg Leu Gly Pro Leu Leu Glu Gln Glu Ile Pro Gln SerVal Pro Gly 85 90 95 Val Gln Thr Leu Leu Gly Ala Gly Arg Gln Ser Leu LeuArg Thr Asn 100 105 110 Lys Ser Cys Lys His Val Val Trp Lys Gly Ser AlaLeu Ala Ala Leu 115 120 125 His Cys Gly Arg Pro Pro Glu Ser Pro Val AsnTyr Gly Ser Pro Pro 130 135 140 Ser Ile Ala Asp Thr Leu Phe Ser Arg LysLeu Asn Gly Lys Tyr Arg 145 150 155 160 Leu Glu Arg Leu Val Pro Thr AlaVal Tyr Gln His Met Lys Met His 165 170 175 Lys Arg Ile Leu Gly His LeuSer Ser Val Tyr Cys Val Thr Phe Asp 180 185 190 Arg Thr Gly Arg Arg IlePhe Thr Gly Ser Asp Asp Cys Leu Val Lys 195 200 205 Ile Trp Ala Thr AspAsp Gly Arg Leu Leu Ala Thr Leu Arg Gly His 210 215 220 Ala Ala Glu IleSer Asp Met Ala Val Asn Tyr Glu Asn Thr Met Ile 225 230 235 240 Ala AlaGly Ser Cys Asp Lys Met Ile Arg Val Trp Cys Leu Arg Thr 245 250 255 CysAla Pro Leu Ala Val Leu Gln Gly His Ser Ala Ser Ile Thr Ser 260 265 270Leu Gln Phe Ser Pro Leu Cys Ser Gly Ser Lys Arg Tyr Leu Ser Ser 275 280285 Thr Gly Ala Asp Gly Thr Ile Cys Phe Trp Leu Trp Asp Ala Gly Thr 290295 300 Leu Lys Ile Asn Pro Arg Pro Thr Lys Phe Thr Glu Arg Pro Arg Pro305 310 315 320 Gly Val Gln Met Ile Cys Ser Ser Phe Ser Ala Gly Gly MetPhe Leu 325 330 335 Ala Thr Gly Ser Thr Asp His Ile Ile Arg Val Tyr PhePhe Gly Ser 340 345 350 Gly Gln Pro Glu Lys Ile Ser Glu Leu Glu Phe HisThr Asp Lys Val 355 360 365 Asp Ser Ile Gln Phe Ser Asn Thr Ser Asn ArgPhe Val Ser Gly Ser 370 375 380 Arg Asp Gly Thr Ala Arg Ile Trp Gln PheLys Arg Arg Glu Trp Lys 385 390 395 400 Ser Ile Leu Leu Asp Met Ala ThrArg Pro Ala Gly Gln Asn Leu Gln 405 410 415 Gly Ile Glu Asp Lys Ile ThrLys Met Lys Val Thr Met Val Ala Trp 420 425 430 Asp Arg His Asp Asn ThrVal Ile Thr Ala Val Asn Asn Met Thr Leu 435 440 445 Lys Val Trp Asn SerTyr Thr Gly Gln Leu Ile His Val Leu Met Gly 450 455 460 His Glu Asp GluVal Phe Val Leu Glu Pro His Pro Phe Asp Pro Arg 465 470 475 480 Val LeuPhe Ser Ala Gly His Asp Gly Asn Val Ile Val Trp Asp Leu 485 490 495 AlaArg Gly Val Lys Val Arg Ser Tyr Phe Asn Met Ile Glu Gly Gln 500 505 510Gly His Gly Ala Val Phe Asp Cys Lys Cys Ser Pro Asp Gly Gln His 515 520525 Phe Ala Cys Thr Asp Ser His Gly His Leu Leu Ile Phe Gly Phe Gly 530535 540 Ser Ser Ser Lys Tyr Asp Lys Ile Ala Asp Gln Met Phe Phe His Ser545 550 555 560 Asp Tyr Arg Pro Leu Ile Arg Asp Ala Asn Asn Phe Val LeuAsp Glu 565 570 575 Gln Thr Gln Gln Ala Pro His Leu Met Pro Pro Pro PheLeu Val Asp 580 585 590 Val Asp Gly Asn Pro His Pro Ser Arg Tyr Gln ArgLeu Val Pro Gly 595 600 605 Arg Glu Asn Cys Arg Glu Glu Gln Leu Ile ProGln Met Gly Val Thr 610 615 620 Ser Ser Gly Leu Asn Gln Val Leu Ser GlnGln Ala Asn Gln Asp Ile 625 630 635 640 Ser Pro Leu Asp Ser Met Ile GlnArg Leu Gln Gln Glu Gln Asp Leu 645 650 655 Arg Arg Ser Gly Glu Ala GlyVal Ser Asn Ala Ser Arg Val Asn Arg 660 665 670 Gly Ser Val Ser Ser ThrSer Glu Val His Ser Pro Pro Asn Ile Gly 675 680 685 Leu Arg Arg Ser GlyGln Ile Glu Gly Val Arg Gln Met His Ser Asn 690 695 700 Ala Pro Arg SerGlu Ile Ala Thr Glu Arg Asp Leu Val Ala Trp Ser 705 710 715 720 Arg ArgVal Val Val Pro Glu Leu Ser Ala Gly Val Ala Ser Arg Gln 725 730 735 GluGlu Trp Arg Thr Ala Lys Gly Glu Glu Glu Ile Lys Ser Tyr Arg 740 745 750Ser Glu Glu Lys Arg Lys His Leu Thr Val Ala Lys Glu Asn Lys Ile 755 760765 Leu Thr Val Ser Lys Asn His Ala His Glu His Phe Leu Asp Leu Gly 770775 780 Asp Ser Lys Lys Gln Gln Ala Asn Gln His Asn Tyr Arg Thr Arg Ser785 790 795 800 Ala Leu Glu Glu Thr Pro Arg Pro Leu Glu Glu Leu Glu AsnGly Thr 805 810 815 Ser Ser Ser Asp Glu Gly Glu Val Leu Ala Val Ser GlyGly Thr Ser 820 825 830 Glu Glu Glu Glu Arg Ala Trp His Ser Asp Gly SerSer Ser Asp Tyr 835 840 845 Ser Ser Asp Tyr Ser Asp Trp Thr Ala Asp AlaGly Ile Asn Leu Gln 850 855 860 Pro Pro Lys Lys Val Pro Lys His Lys ThrLys Lys Pro Glu Ser Ser 865 870 875 880 Ser Asp Glu Glu Glu Glu Ser GluAsn Gln Lys Gln Lys His Ile Lys 885 890 895 Lys Glu Arg Lys Lys Ala AsnGlu Glu Lys Asp Gly Pro Thr Ser Pro 900 905 910 Lys Lys Lys Lys Pro LysGlu Arg Lys Gln Lys Arg Leu Ala Val Gly 915 920 925 Glu Leu Thr Glu AsnGly Leu Thr Leu Glu Glu Trp Leu Pro Ser Ala 930 935 940 Trp Ile Thr AspThr Leu Pro Arg Arg Cys Pro Phe Val Pro Gln Met 945 950 955 960 Gly AspGlu Val Tyr Tyr Phe Arg Gln Gly His Glu Ala Tyr Val Glu 965 970 975 MetAla Arg Lys Asn Lys Ile Tyr Ser Ile Asn Pro Lys Lys Gln Pro 980 985 990Trp His Lys Met Glu Leu Arg Val Asn Ile Gly Ile Phe Phe Asn Val 995 10001005 Lys Tyr Ile Phe Cys Ile Ile Arg Glu Val Val Arg Phe Thr Leu 10101015 1020 Leu Glu Thr Gly Ala Gly Glu Glu Phe Arg Arg Tyr Ala Ser Met1025 1030 1035 Lys Val Arg Leu Pro Gly Ser Gly Gly Ala His Leu Ser GlnHis 1040 1045 1050 Leu Gly Gly Arg Gly Arg Met Ser Arg Glu Arg Lys Gly1055 1060 1065 39 142 DNA Homo sapiens 39 ccgaagctcg gctcgtgaacacacactgac agctataggg caggcggcgg caccgtcccc 60 gcttcccctc ggcggcggggtgtcccgtcg gcggccctga agtgacccat aaacatgtct 120 tgtgagagga aaggcctctc gg142 40 71 DNA Homo sapiens 40 agctgcgatc ggagctctac ttcctcatcgcccggttcct ggaagatgga ccctgtcagc 60 aggcggctca g 71 41 30 DNA Homosapiens 41 gtgctgatcc gcgaggtggc cgagaaggag 30 42 60 DNA Homo sapiens 42ctgctgcccc ggcgcaccga ctggaccggg aaggagcatc ccaggaccta ccagaatctg 60 43151 DNA Homo sapiens 43 gtgaagtatt acagacactt agcacctgat cacttgctgcaaatatgtca tcgactagga 60 cctcttcttg aacaagaaat tcctcaaagt gttcctggagtacaaacttt attaggagct 120 ggaagacagt ctttactacg cacaaataaa a 151 44 99DNA Homo sapiens 44 gctgcaagca tgttgtgtgg aaaggatctg ctctggctgcgttgcactgt ggaagaccac 60 ctgagtcacc agttaactat ggtagcccac ccagcattg 9945 161 DNA Homo sapiens 45 cggatactct gttttcaagg aagctgaatg ggaaatacagacttgagcga cttgttccaa 60 ctgcagtgta tcagcacatg aaaatgcata aacgaattcttggacacttg tcatctgtgt 120 actgtgtaac ttttgatcga actggcagac ggatatttac t161 46 222 DNA Homo sapiens 46 ggttctgatg actgtcttgt gaaaatatgggcaacagatg atgggaggtt gttagctacc 60 ttaagaggac atgctgctga aatatcagacatggctgtaa actatgagaa taccatgata 120 gcagctggaa gttgtgataa aatgatccgagtctggtgtc ttcgaacctg tgcacctttg 180 gctgttcttc agggccatag tgcatctattacatcactac ag 222 47 101 DNA Homo sapiens 47 ttctcaccat tgtgcagtggctcaaagaga tatctatctt ctactggggc agatggcact 60 atttgttttt ggctctgggatgctggaacc cttaaaataa a 101 48 71 DNA Homo sapiens 48 cccaagacctgcaaaattta cagagcgccc tcggcctgga gttcaaatga tctgttcttc 60 ttttagtgct g71 49 101 DNA Homo sapiens 49 gtggaatgtt tctggcgacg ggaagcacagatcatattat tcgggtttat ttttttggat 60 caggtcagcc agagaaaata tcagaattggagtttcatac t 101 50 41 DNA Homo sapiens 50 gacaaagttg acagtatccagttttccaac actagtaaca g 41 51 99 DNA Homo sapiens 51 gtttgtaagtggcagtcgtg atgggacagc acgtatttgg caatttaaac gaagagagtg 60 gaagagcattttgttggata tggctactcg tccagcagg 99 52 154 DNA Homo sapiens 52 ccaaaaccttcaaggaatag aagataaaat cacaaaaatg aaggttacta tggtagcttg 60 ggatcgacatgacaatacag ttataactgc agttaataac atgactctga aagtttggaa 120 ttcttacactggtcaactaa ttcatgtcct gatg 154 53 135 DNA Homo sapiens 53 ggtcatgaagatgaggtatt tgttcttgaa ccacacccgt tcgatcctag agttctcttt 60 tctgctggtcatgatggaaa cgtgatagtg tgggatctgg caagaggagt caaaatacga 120 tcttatttcaatatg 135 54 129 DNA Homo sapiens 54 attgaaggcc aaggacatgg cgcagtatttgactgcaaat gctctcctga tggtcagcat 60 tttgcatgca cagactctca tggacatcttttaatttttg gctttgggtc cagtagcaaa 120 tatgacaag 129 55 226 DNA Homosapiens 55 atagcagatc agatgttctt tcatagtgat tatcggccac ttattcgtgatgccaacaat 60 tttgtattag atgaacagac tcagcaagca cctcatctta tgcctcccccttttttggtt 120 gatgttgatg gtaaccctca tccatcaaga tatcaaagat tagttcctggccgtgaaaat 180 tgcagggagg agcaactcat ccctcagatg ggagtaactt cctcag 226 56138 DNA Homo sapiens 56 gactgaatca agttttaagt cagcaagcaa accaggagatcagcccactg gacagcatga 60 ttcaaagact acaacaggag caagacctga gacgttctggtgaagcagtt atcagtaata 120 ccagccgttt aagtagag 138 57 184 DNA Homosapiens 57 gctccataag ttctacctca gaggttcatt caccaccaaa cgtaggactaagacgtagtg 60 gacaaattga aggtgtacgg caaatgcaca gcaacgcacc aagaagtgaaatagccacag 120 agcgggatct ggtagcttgg agtcgaaggg tggtagtacc cgagctatcagctggtgtag 180 ccag 184 58 118 DNA Homo sapiens 58 taggcaagaa gaatggagaactgcaaaggg agaagaagaa ataaagactt acaggtcaga 60 agagaaaaga aaacacttaactgttccaaa agagaataaa atacccactg tctcaaag 118 59 141 DNA Homo sapiens 59aatcatgctc atgagcattt cctggatctt ggagaatcca aaaagcaaca gacaaatcaa 60cacaattatc gtacaagatc tgcattggaa gagactccta gaccctcaga agagatagaa 120aatggcagta gttcttcaga t 141 60 77 DNA Homo sapiens 60 gaaggcgaagtagttgctgt cagtggtgga acatccgaag aagaagagag agcatggcac 60 agtgatggcagttctag 77 61 232 DNA Homo sapiens 61 tgactactcc agtgattact ctgactggacagcagatgca ggaattaatc tgcagccacc 60 aaagaaagtt cctaagaata aaaccaagaaagcagaaagc agttcagatg aagaagaaga 120 atctgaaaaa cagaagcaaa aacagattaaaaaggaaaag aaaaaagtaa atgaagaaaa 180 agatggacca atatcaccaa agaaaaagaagcccaaagaa agaaaacaaa ag 232 62 120 DNA Homo sapiens 62 agattggctgtgggagaact aactgaaaat ggtttgacat tagaagaatg gttgccatca 60 acatggattacagataccat tccccgaaga tgtccatttg tgccacagat gggtgatgag 120 63 108 DNAHomo sapiens 63 gtttattatt tccgacaagg acatgaagcc tatgtcgaaa tggcccggaaaaataaaata 60 tatagtatca atcccaaaaa acaaccatgg cataaaatgg agctacgg 10864 996 PRT Homo sapiens 64 Ser Ser Ala Arg Arg Pro Val Pro Leu Ile GluSer Glu Leu Tyr Phe 1 5 10 15 Leu Ile Ala Arg Tyr Leu Ser Ala Gly ProCys Arg Arg Ala Ala Gln 20 25 30 Val Leu Val Gln Glu Leu Glu Gln Tyr GlnLeu Leu Pro Lys Arg Leu 35 40 45 Asp Trp Glu Gly Asn Glu His Asn Arg SerTyr Glu Glu Leu Val Leu 50 55 60 Ser Asn Lys His Val Ala Pro Asp His LeuLeu Gln Ile Cys Gln Arg 65 70 75 80 Ile Gly Pro Met Leu Asp Lys Glu IlePro Pro Ser Ile Ser Arg Val 85 90 95 Thr Ser Leu Leu Gly Ala Gly Arg GlnSer Leu Leu Arg Thr Ala Lys 100 105 110 Asp Cys Arg His Thr Val Trp LysGly Ser Ala Phe Ala Ala Leu His 115 120 125 Arg Gly Arg Pro Pro Glu MetPro Val Asn Tyr Gly Ser Pro Pro Asn 130 135 140 Leu Val Glu Ile His ArgGly Lys Gln Leu Thr Gly Cys Ser Thr Phe 145 150 155 160 Ser Thr Ala PhePro Gly Thr Met Tyr Gln His Ile Lys Met His Arg 165 170 175 Arg Ile LeuGly His Leu Ser Ala Val Tyr Cys Val Ala Phe Asp Arg 180 185 190 Thr GlyHis Arg Ile Phe Thr Gly Ser Asp Asp Cys Leu Val Lys Ile 195 200 205 TrpSer Thr His Asn Gly Arg Leu Leu Ser Thr Leu Arg Gly His Ser 210 215 220Ala Glu Ile Ser Asp Met Ala Val Asn Tyr Glu Asn Thr Met Ile Ala 225 230235 240 Ala Gly Ser Cys Asp Lys Ile Ile Arg Val Trp Cys Leu Arg Thr Cys245 250 255 Ala Pro Val Ala Val Leu Gln Gly His Thr Gly Ser Ile Thr SerLeu 260 265 270 Gln Phe Ser Pro Met Ala Lys Gly Ser Gln Arg Tyr Met ValSer Thr 275 280 285 Gly Ala Asp Gly Thr Val Cys Phe Trp Gln Trp Asp LeuGlu Ser Leu 290 295 300 Lys Phe Ser Pro Arg Pro Leu Lys Phe Thr Glu LysPro Arg Pro Gly 305 310 315 320 Val Gln Met Leu Cys Ser Ser Phe Ser ValGly Gly Met Phe Leu Ala 325 330 335 Thr Gly Ser Thr Asp His Val Ile ArgMet Tyr Phe Leu Gly Phe Glu 340 345 350 Ala Pro Glu Lys Ile Ala Glu LeuGlu Ser His Thr Asp Lys Val Asp 355 360 365 Ser Ile Gln Phe Cys Asn AsnGly Asp Arg Phe Leu Ser Gly Ser Arg 370 375 380 Asp Gly Thr Ala Arg IleTrp Arg Phe Glu Gln Leu Glu Trp Arg Ser 385 390 395 400 Ile Leu Leu AspMet Ala Thr Arg Ile Ser Gly Asp Leu Ser Ser Glu 405 410 415 Glu Glu ArgPhe Met Lys Pro Lys Val Thr Met Ile Ala Trp Asn Gln 420 425 430 Asn AspSer Ile Val Val Thr Ala Val Asn Asp His Val Leu Lys Val 435 440 445 TrpAsn Ser Tyr Thr Gly Gln Leu Leu His Asn Leu Met Gly His Ala 450 455 460Asp Glu Val Phe Val Leu Glu Thr His Pro Phe Asp Ser Arg Ile Met 465 470475 480 Leu Ser Ala Gly His Asp Gly Ser Ile Phe Ile Trp Asp Ile Thr Lys485 490 495 Gly Thr Lys Met Lys His Tyr Phe Asn Met Ile Glu Gly Gln GlyHis 500 505 510 Gly Ala Val Phe Asp Cys Lys Phe Ser Gln Asp Gly Gln HisPhe Ala 515 520 525 Cys Thr Asp Ser His Gly His Leu Leu Ile Phe Gly PheGly Cys Ser 530 535 540 Lys Pro Tyr Glu Lys Ile Pro Asp Gln Met Phe PheHis Thr Asp Tyr 545 550 555 560 Arg Pro Leu Ile Arg Asp Ser Asn Asn TyrVal Leu Asp Glu Gln Thr 565 570 575 Gln Gln Ala Pro His Leu Met Pro ProPro Phe Leu Val Asp Val Asp 580 585 590 Gly Asn Pro His Pro Thr Lys TyrGln Arg Leu Val Pro Gly Arg Glu 595 600 605 Asn Ser Ala Asp Glu His LeuIle Pro Gln Leu Gly Tyr Val Ala Thr 610 615 620 Ser Asp Gly Glu Val IleGlu Gln Ile Ile Ser Leu Gln Thr Asn Asp 625 630 635 640 Asn Asp Glu ArgSer Pro Glu Ser Ser Ile Leu Asp Gly Met Ile Arg 645 650 655 Gln Leu GlnGln Gln Gln Asp Gln Arg Met Gly Ala Asp Gln Asp Thr 660 665 670 Ile ProArg Gly Leu Ser Asn Gly Glu Glu Thr Pro Arg Arg Gly Phe 675 680 685 ArgArg Leu Ser Leu Asp Ile Gln Ser Pro Pro Asn Ile Gly Leu Arg 690 695 700Arg Ser Gly Gln Val Glu Gly Val Arg Gln Met His Gln Asn Ala Pro 705 710715 720 Arg Ser Gln Ile Ala Thr Glu Arg Asp Leu Gln Ala Trp Lys Arg Arg725 730 735 Val Val Val Pro Glu Val Pro Leu Gly Ile Phe Arg Lys Leu GluAsp 740 745 750 Phe Arg Leu Glu Lys Gly Glu Glu Glu Arg Asn Leu Tyr IleIle Gly 755 760 765 Arg Lys Arg Lys Thr Leu Gln Leu Ser His Lys Ser AspSer Val Val 770 775 780 Leu Val Ser Gln Ser Arg Gln Arg Thr Cys Arg ArgLys Tyr Pro Asn 785 790 795 800 Tyr Gly Arg Arg Asn Arg Ser Trp Arg GluLeu Ser Ser Gly Asn Glu 805 810 815 Ser Ser Ser Ser Val Arg His Glu ThrSer Cys Asp Gln Ser Glu Gly 820 825 830 Ser Gly Ser Ser Glu Glu Asp GluTrp Arg Ser Asp Arg Lys Ser Glu 835 840 845 Ser Tyr Ser Glu Ser Ser SerAsp Ser Ser Ser Arg Tyr Ser Asp Trp 850 855 860 Thr Ala Asp Ala Gly IleAsn Leu Gln Pro Pro Leu Arg Thr Ser Cys 865 870 875 880 Arg Arg Arg IleThr Arg Phe Cys Ser Ser Ser Glu Asp Glu Ile Ser 885 890 895 Thr Glu AsnLeu Ser Pro Pro Lys Arg Arg Arg Lys Arg Lys Lys Glu 900 905 910 Asn LysPro Lys Lys Glu Asn Leu Arg Arg Met Thr Pro Ala Glu Leu 915 920 925 AlaAsn Met Glu His Leu Tyr Glu Phe His Pro Pro Val Trp Ile Thr 930 935 940Asp Thr Thr Leu Arg Lys Ser Pro Phe Val Pro Gln Met Gly Asp Glu 945 950955 960 Val Ile Tyr Phe Arg Gln Gly His Glu Ala Tyr Ile Glu Ala Val Arg965 970 975 Arg Asn Asn Ile Tyr Glu Leu Asn Pro Asn Lys Glu Pro Trp ArgLys 980 985 990 Met Asp Leu Arg 995 65 183 PRT Homo sapiens 65 Leu ProHis Arg Asn Ala Ser Ala Val Ala Arg Lys Lys Leu Leu His 1 5 10 15 AsnSer Glu Asp Glu Gln Ser Leu Lys Ser Glu Ile Glu Glu Glu Glu 20 25 30 LeuLys Asp Glu Asn Gln Leu Leu Pro Val Ser Ser Ser His Thr Ala 35 40 45 GlnSer Asn Val Asp Glu Ser Glu Asn Arg Asp Ser Glu Ser Glu Ser 50 55 60 AspLeu Arg Val Ala Arg Lys Asn Trp His Ala Asn Gly Tyr Lys Ser 65 70 75 80His Thr Pro Ala Pro Ser Lys Thr Lys Phe Leu Lys Ile Glu Ser Ser 85 90 95Glu Glu Asp Ser Lys Ser His Asp Ser Asp His Ala Cys Asn Arg Thr 100 105110 Ala Gly Pro Ser Thr Ser Val Gln Lys Leu Lys Ala Glu Ser Ile Ser 115120 125 Glu Glu Ala Asp Ser Glu Pro Gly Arg Ser Gly Gly Arg Lys Tyr Asn130 135 140 Thr Phe His Lys Asn Ala Ser Phe Phe Lys Lys Thr Lys Ile LeuSer 145 150 155 160 Asp Ser Glu Asp Ser Glu Ser Glu Glu Gln Asp Arg GluAsp Gly Lys 165 170 175 Cys His Lys Met Glu Met Asn 180 66 205 PRT Musmusculus 66 Arg Leu Ala Val Gly Glu Leu Thr Glu Asn Gly Leu Thr Leu GluGlu 1 5 10 15 Trp Leu Pro Ser Ala Trp Ile Thr Asp Thr Leu Pro Arg ArgCys Pro 20 25 30 Phe Val Pro Gln Met Gly Asp Glu Val Tyr Tyr Phe Arg GlnGly His 35 40 45 Glu Ala Tyr Val Glu Met Ala Arg Lys Asn Lys Ile Tyr SerIle Asn 50 55 60 Pro Lys Lys Gln Pro Trp His Lys Met Glu Leu Arg Glu GlnGlu Leu 65 70 75 80 Met Lys Ile Val Gly Ile Lys Tyr Glu Val Gly Leu ProThr Leu Cys 85 90 95 Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr Gly LysLeu Thr Gly 100 105 110 Gly Ser Phe Thr Met Lys Tyr His Asp Met Pro AspVal Ile Asp Phe 115 120 125 Leu Val Leu Arg Gln Gln Phe Asp Asp Ala LysTyr Arg Arg Trp Asn 130 135 140 Ile Gly Asp Arg Phe Arg Ser Val Ile AspAsp Ala Trp Trp Phe Gly 145 150 155 160 Thr Ile Glu Ser Gln Glu Pro LeuGln Pro Glu Tyr Pro Asp Ser Leu 165 170 175 Phe Gln Cys Tyr Asn Val CysTrp Asp Asn Gly Asp Thr Glu Lys Met 180 185 190 Ser Pro Trp Asp Met GluLeu Ile Pro Asn Asn Ala Val 195 200 205 67 166 PRT Artificial Sequencemutant DN-mPHIP #1 67 Arg Leu Ala Val Gly Glu Leu Thr Glu Asn Gly LeuThr Leu Glu Glu 1 5 10 15 Trp Leu Pro Ser Ala Trp Ile Thr Asp Thr LeuPro Arg Arg Cys Pro 20 25 30 Phe Val Pro Gln Met Gly Asp Glu Val Tyr TyrPhe Arg Gln Gly His 35 40 45 Glu Ala Tyr Val Glu Met Ala Arg Lys Asn LysIle Tyr Ser Ile Asn 50 55 60 Pro Lys Lys Gln Pro Trp His Lys Met Glu LeuArg Glu Gln Glu Leu 65 70 75 80 Met Lys Ile Val Gly Ile Lys Tyr Glu ValGly Leu Pro Thr Leu Cys 85 90 95 Cys Leu Lys Leu Ala Phe Leu Asp Pro AspThr Gly Lys Leu Thr Gly 100 105 110 Gly Ser Phe Thr Met Lys Tyr His AspMet Pro Asp Val Ile Asp Phe 115 120 125 Leu Val Leu Arg Gln Gln Phe AspAsp Ala Lys Tyr Arg Arg Trp Asn 130 135 140 Ile Gly Asp Arg Phe Arg SerVal Ile Asp Asp Ala Trp Trp Phe Gly 145 150 155 160 Thr Ile Glu Ser GlnGlu 165 68 152 PRT Artificial Sequence mutant DN-mPHIP #2 68 Glu Glu TrpLeu Pro Ser Ala Trp Ile Thr Asp Thr Leu Pro Arg Arg 1 5 10 15 Cys ProPhe Val Pro Gln Met Gly Asp Glu Val Tyr Tyr Phe Arg Gln 20 25 30 Gly HisGlu Ala Tyr Val Glu Met Ala Arg Lys Asn Lys Ile Tyr Ser 35 40 45 Ile AsnPro Lys Lys Gln Pro Trp His Lys Met Glu Leu Arg Glu Gln 50 55 60 Glu LeuMet Lys Ile Val Gly Ile Lys Tyr Glu Val Gly Leu Pro Thr 65 70 75 80 LeuCys Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr Gly Lys Leu 85 90 95 ThrGly Gly Ser Phe Thr Met Lys Tyr His Asp Met Pro Asp Val Ile 100 105 110Asp Phe Leu Val Leu Arg Gln Gln Phe Asp Asp Ala Lys Tyr Arg Arg 115 120125 Trp Asn Ile Gly Asp Arg Phe Arg Ser Val Ile Asp Asp Ala Trp Trp 130135 140 Phe Gly Thr Ile Glu Ser Gln Glu 145 150 69 140040 DNA Homosapiens misc_feature (1)..(189) introns 69 gaattcatta tagatcaatttctttcgttt caaacagtga atgaaatgaa tgtgaaaatg 60 cataacctat ctaagggcaataaatagcaa acatttaaaa tatatatgta tatatttata 120 tatatatata tattcatttaaagaagtgaa gtgtctcgta agtttgtttt tttttttttt 180 tttttttttg caaatcaaatcataacattc cctactccac cacagcagca aggaagcaga 240 agccttagtt ctacttattccttaactgta cctgctttat agattttgaa gtaaaatatt 300 ttggtacaag ttaccaaccaattaaattag cttttgcttt ttcagtcaac tttcggactc 360 gtcctctact agaagttccaaaagttaaag aggtgtcttc gaacaacagc tgcctttgct 420 cctcttcaga gtcatcctcattatagaaag ctgtccttcg accttgattt ctagttctca 480 tgtggggttc agagcctttgagttcttcaa actcttcttc ctcatctata ggatcatcta 540 tcttttttcg gttacttctccttaacactt tgacacttgc agggactagg agatctgcat 600 ctaatttttg tgtcttcatcttccttttgg gcttcctacc tccacgattc tttttctgta 660 acaaatcttc ctttacattattagtttcag aaagaaaatt gcatgttgaa gaaggaagta 720 cttcatctct gatgggatgcacattatttt gctctaaatc ttctggcttt gcatactgta 780 gctttttggg ctttctaccccttttcttgt gtataatttc accactattg gtattaactt 840 ctactttagg tttccttccaggtcccctct tcacaagttt tgatggctgt cctccatggc 900 catttacttg aatggttcctggtacaagag cgttgttctt acaatctcct aaaagggaac 960 aacagtacac ttaatatatggagtttcttt ttttgtttga ctctcaaact tgtcagtaag 1020 gccccattgg tatacttatatgtaatgaca taatccaaat tattttatta aaatgagaaa 1080 aaagaaccta gaaaacactaatagttcaat gatcttattt attttctaat taaaagagac 1140 agattcttaa cgatctcatgagggaggtaa agctcataga aaataagtga cttatctaag 1200 ttaacattgt gattgagtataaagctggga tgactaaagg tttcttattc ctaacttaga 1260 aataagttac tcttggtcaaaaactttgtt cttagaactg tttaaagagg atttaaaaac 1320 aactaaatgg cagttttcacaggctttgaa aagtcctatc tccttgtgta ataaatggca 1380 aatgactata atcctaggaaatactgatta tatatatata tcaatcaaaa tcactatgtg 1440 tgccaccatt atcatgattaagatcccact gtaacaaact ccatgataaa aggccattat 1500 gcttcataaa acaggagagaaaatctggca atcaaattct aaacctgaag gatctggaga 1560 tgatgaatta cctttctgttgtagaaaaaa atgctataac ttagataaag gaaaaatatg 1620 ccacaggaac taccagtaactaactctctt tccctccaaa tttctgacat gtttttattt 1680 gatatggtag gtgatttgcaatgctctatt tttgaggaaa ttcatagatg gaaactgctt 1740 ttaaagagaa tacatcttcataacagcatt tttggtcaca ggttggaact gtactttgta 1800 aataagaaaa tcatggttggtcgggtgcag tggctcacga ttataatccc agcactctgg 1860 gaggccaaag tgggcggatcacctgaggtc aggagttcga gaccagcctg gccaacatgg 1920 cgaaaccccg tctctactaaaagtacaaaa agtagctggg cgtggtggtg ggtgcctgta 1980 atcccagcta ctcagggggctgaggcagga gaatcctttg aacccaggag gcggaggttg 2040 cagtgagctg agatcacgccactgcactcc agcctgggcg acaagaggga gactccatct 2100 caaaaacaaa acaaaacaaaacaaaacaac atggttaaga gacttaccaa aggtcagagc 2160 caagtacaga cagaaaatgcaaagctttta attcctgacc cccatagtga aatgactctc 2220 tttagattag tggttgggaaaaaatgtggg tgtggacata aagtagttaa gtatttccta 2280 tggagcaact gacatttaaactgcccaggg attctgtcaa tctcttttgt tttacattat 2340 gactacaagg gttctaaatatccagtacat gtacctacta cagaagatag gctttaagga 2400 ctacatgaat cccttgtaatggtcccaaat tttgtatgga tatgtttatg tacatttttc 2460 tgagacaggg actataggactcatcaactt tataaagcaa tatataatgt aaaaaggtta 2520 agaatgaatg cagctttcttaaaaaggaat tcagaagttt tttaaaaaag tttaaaaacc 2580 actgatattg aacggtgttgtcctgggcac atgaaaagtt atgcagctta ggaactaaat 2640 ttttatttaa atttcaatttaaataccaaa gcagtataca ttttaaaata ctgattaaat 2700 actgaaataa cattttggatataatgggat aaataaaata ttattaaaat taactttacc 2760 tgtttttact gaacatggtgagtacaaaat ttaaaattac atatatggct tgtattatat 2820 tccactagac aacactgcttgattctaaat agttaattta ggtgtcatta tttgtaataa 2880 aacactgtta atgttaactaatagataatg atatttctat acagtaccag tactcgagta 2940 tttgtaatac tcaaaaattaaaaatcaaac aggttatgat accagacctc cgctatcata 3000 atgctagaac caattcatcatatatatttg atttctctag gattcatgaa taaaaagaag 3060 caaggccaat atactattcaaactctaaat tcagttcaga aagggggcag attattaaaa 3120 atgtgaaaca ctcatatgcaaagcattttg gttattcaaa cacttattat cttctgtata 3180 atgggcatta aaaatgagtaaacacattaa gctcagattc tttggagata cagacatgtg 3240 aaaatgaata atatgatcaacattataagt accaccaaag gtaatgaaca gggttttctg 3300 ggacataaag atggaagtgcttggctgggc gtggtggctc acatctgaaa tcacaatact 3360 ttgggaggcc gagtggggtggatcaccaga ggccagaagt ttgagaccag cctggtcaaa 3420 atggtgaaat cctgtctatatcaaaaatac aaaatcagcc aggtgtgatg gcacacacct 3480 ataattccag ctacttgggaggctgaggca gaagaattgc ttgaaccggc aaggcagagg 3540 ttgcagtgaa tggaaatcaggccattgcac ttcagcctcg gtgacagagc aagatcctgt 3600 ctttttttaa aaaaaaaaaaaaaaaaaaaa aggaagtgct tgattctatc taaagaagcc 3660 aggagaagac ttcctaaagaagacgatatt ttaagtgaga cgtgaaaggc aacagacaat 3720 taaactagga gggaaaaaaagacattcccc caaaaggaga aaagaacaaa gactcaggaa 3780 cttctaagtg tttaggatgactgggataca aaagagagaa agaaggtaaa agaacctgga 3840 atgttaggca agagccaagtaataaagagt cttgtgtaac aggcaaaaaa tttaaaatgt 3900 ttccatatat gatttgaaggcaaggaagtg ttttctctgt gtgtacgtac acacatccac 3960 atgtgctaga gagaaataaaaagatcgctt tggctgcaat atgagagagg gactggttaa 4020 gaaagagttg agaactgaggcaggaagacc agttaggaaa ctaggaaaat agtccaagca 4080 agaaattatg taggccttgaaataatgtca tggaggtgag aatggagagg agagaataga 4140 tttaagagat gttatggagggagaaacaac aaaaacaaaa agctgttgaa cagattcagt 4200 tgctgaagag aaggctaggatgactccctg attttaagtt tacacgggta gatcccaatg 4260 ccattaacaa aaataagatttcagtagaga aattaaattt tgagagaggt ttctgaagac 4320 aacaatgaag aaatgtcttagacacacttt gaaagtcatg atgcaaaatg cttattattg 4380 ggctgtctgc tgccaagaagccatattatt ttaacatgtc acatggcata ttttattatt 4440 taccttcttc atctttcaaacataaagact ttacaataaa aacctggagg tgaaagaact 4500 tgaagtgtaa cagtaaggtgtcaaaagttg tattctacag ttgtagacaa ccccaatgaa 4560 ttattattta gtaaaagtcagtctagaaaa ataagtagtt ttgtgatcca ataattactt 4620 aaacattttt ctagaaaagtgaagaatgct acattgggtt aactataccc tatttaattt 4680 aaactttgaa gatttatttctttttttttt ttttcttttg agacagggtc tcattctgtt 4740 taccaggatg gagtgcagtggcacaataat agctcattgc agtaaattta tcaactaata 4800 cagatgtgtg acttttaagtgggcaacctg aaaagtggat ataaatgctg attccaacaa 4860 aagcattatt tataataaggatctactgta tcttgaaaga tacaagtaat accttacctt 4920 gctcaatgac agctgatgactttgaaagag tggacgcctt tgggagtaca gatgacttca 4980 ttttacgttt gactggcttttccttttcca tgttttcttt tgcagaatta ttcctagtgc 5040 catgactaaa actggattgaccaggactgg aaagagtatt caaagctttg gaatgtttca 5100 cagaattctc tagtactaaaacatacaaac aaaatttaaa aattaagagt tattgaacct 5160 aaagataaga aaaaaggttaacctgaatta tttgaattag ccaagacaac aaaacctgaa 5220 ggatgcttaa agctttcttaggaaagctac tttctaatag gaaaaaggcg tatccaacta 5280 gaaactctta atagtttcagcccttttaga agctgtccca tcatttcaaa atttcgaagg 5340 caagtcttgg caaattgctagctagtgtgg gtactgtgat ttaaattcag gtagtttaga 5400 tcagagttgc catttttaagcattagtcta taatgaccta aacctcaatt taattcttct 5460 tattaaaaac ttttttttaaaataggaaat taataaagaa ggcaaaaaca acagtgtctg 5520 ctaggaatta ctaaaactcagtatattgca tttggcaaag taaaagctta aattaagaaa 5580 atcatcatat acatttcaatttagaaagtg agtcttactt gttttccctg gtattgcaga 5640 tgcattagct tttgtaataaaagtctttgc agctgaagaa gtagatggtt gctcagtgac 5700 aactggatct acaaccactcggttgcttct ggttcgaacc acagaactag attctgtttt 5760 accgtttatc tgagcagcattgtgtcttgg cggtattgat cgtgtaggtg tagagaatgc 5820 agaggtagag ctttctgattttagctgggg ttttaagatc ctttttttcc tttcagggct 5880 gtaaataaaa tagtattgtcagtcactctt atagctctat gtgaacgaat aaaacagttt 5940 ataatatttt tggattcaatatttgtacta ttatgaaata tgttaaaata tgagatttat 6000 agtggatttc atatgattgtgagcctttga aagtgaatat ttagtgaagg atcgctgtaa 6060 atgctaaagt tatatgacggaaagcatgat gccatcacta tcctaaaaat gctgttttac 6120 tgtatagatt tagcagtttgaatttaagca cttacactag tatagcttta gttaaaagat 6180 taaaaatcct ccacatcataggaacttgca tgtcaaatta tcattctgca atatagggaa 6240 tagtaaagga agtattaaaaaacaccaagt tctatcattt agatgaaagt tatagatcag 6300 ctagtggtat ttaaaagaaattaaatacct tgatgcagca ctactggaaa cagagctgct 6360 tctgtttctt ttcttcctccttttggttat ggtatttctt ttatgaaaac gaagagcaga 6420 tttataatct gataaaactgaactaatgtg ttcttcaaag aaagcagaca ggcgcaaact 6480 catgctgtaa atctgtgagggaaaaaaaaa agtgttcaac cattccttgg aggaaaatac 6540 ctttgttcag taaatactgtaatgtaaata tttttccagt aaaaaatatt tagaatttaa 6600 ttattgtttt ttacatccctttttcctaat cttttgatga aaaggtaaac tgaagcattt 6660 taacaattat gtatttttgtgtttagaaca gaaatcttcc aagttttgag attcttaaag 6720 aaaagtccga ctctaaattcaaatggctca tacagacaaa acttattgtc aactttatta 6780 cactgaaact atcccaaatgtttgaacctg ttttctatct aggactagca tctattcttt 6840 ctcatttcgt tgctatatagcactcctttg tgatgtcatg tctggtcaga gtgttaaatt 6900 atatttttac ttatttgtaaaaatcttcgc aaaaatgctc cacaaggcag ataatagcta 6960 gaaaactcaa ggccagatggctctggtgca taccaggaca atttgcatca accgcactac 7020 ttcaagaaaa gtaaccattcccagacatca aagataacat caatgttatt tcatacaagg 7080 agctgagtag aaaggtataatttctttttc cagtaggaca acattaagaa tgtaacagaa 7140 agttaacttt gacctaaattttaagtaaag caacatttag tcatttaaca cactcctcta 7200 acttaatcta gtcataaaagaaaataatgt aattatatac ccttgatctt ttgcttggtg 7260 tatatgcttt ggaattactgaaaataagtc tgacatcttt acataactcc attggtgact 7320 cataattccc agcctctaaagtttctctaa cggtagcaaa atccattgga gtgtcaatga 7380 tgtctctgta gtcctaggagagggaaaaca ggtggtgtta tgattattac tacacaaagc 7440 atcacttctc agtgcagggattcgcacagg atttttatga tgactgcaag tcctagaact 7500 cttaataatc actcctgttccccttatcaa gagtcccttt tttctaataa ttcttattta 7560 tttcatactc cccccccttatactgcaatc aacaataatt ttcttattca agaacacaga 7620 agttattaat ttttcactggagacttggga gatggagttg tattggaaaa gggaaagtaa 7680 aagagtaagg aaaaagcccagctctacaac cgaaagtttg aaagaaaaac tcaaaacttt 7740 atactactta taaattctaaaggtctgact cattaaaaca caactgtaac tttaaggaaa 7800 taaaaacaat ggaagtatgccagcatccca tttatgcaga cacctaagtt ctagtaatct 7860 caacttcagt actaaaattgggagttttgc tttgcagtaa taaagaatta cgaatgtaaa 7920 tagttgtcac aaagtctatgcatgtcacct gagatgtcta cctagtcaat agagtataaa 7980 attaggtaac agattggaaccaataaaaac acacacgtga aacaggaaga gcaacagaaa 8040 attatcataa tatggtatataattctaaaa ttatcagaat atgctatttt tttttagcag 8100 ggacaaagag tattgtaccccccctttttg ggagacacag tcttgctgct gcccaggtta 8160 gagtgcagtt ggtgccatcaaagctcactg catccttggc ctcccagact caagcaacct 8220 tcccacctca gcctctcaagtagcggggac tacaggcagg cgctaccaca cccagctaat 8280 ttttataatt tttgtagagacgggtcttag catgttgctg agactggtct caaactcctg 8340 ggcttaaatg acctgcccgtcttgacctcc caaagtgctg ggattatagg cattagccac 8400 cacacctggc ctgcagcttttcaacagtcc ctcagtatgc gactatattt tttgaagtgt 8460 aacaacttga ctttgcaccatcaagtttaa attatgatca aatacgtctg accatgaaga 8520 aggtgtccta taaggtaggattactgcctt tacaaatttt tatttcttcc tttccaatag 8580 ttatgccttt tatttccttttcttgcctta ttgcattggc tagaatttcc agtactacat 8640 tgaatagcag tggtgagagtgaacattttt cagtcattcc taattcttag ggggaaagca 8700 ctcagtctgt caccagtaaacatgatatta gctgtagatg tactttttat agatgtactt 8760 tatcaagttg tggaagttttcctttgttcc cggttttctt aggggtttta taatgaatta 8820 atgtctcact tcttcagattctgcatttgt ctatttgcca tctattcaca ggccaatgat 8880 gatctggtac ctggggggccttacagacct gggaaaagat tgccccttcc tgggcagtct 8940 tagtgagggg ttccactgagaacatgtctt tcatatacat accaatgaat cccaagtata 9000 aagccacaat cagctccttttctcactctc acacactaag ccagtatttc cctgttttaa 9060 atcatctcag agctgggaccagacaactag atacctgtgc cccagggccc actggaatta 9120 ttcaaactag ccaataataagctgttaact gtgacctgcc ttgcatttcc tgcagaaacc 9180 ccaataaagg atttctaagcttttccctgg ttttggtctc tcctacccaa ccaaaaccta 9240 gcacttcccc tgtggccctgtgtggcatgt ggtaagcccc gacttttctg ggactctttt 9300 ttactttttt ttttttgttgttaatgagat agggtctcac tctattgcca ggctagagtt 9360 cagtggtatc atcttggctcactgcaatgt ctacctccca ggctcaagca atcctcccac 9420 ctcagcctca ttagtagcttgaactatagg tgcacgccac tgcacccggt taatttttgt 9480 attttttgta aagacggggttttgccatat tgctcagact ggtctcaaac tcctgagctc 9540 aagtgatcca cctaccttggcctcccaaag tgctgggatt acaggtgtga gccaccatgc 9600 ttggcctggg actcgagtataataaacttt ttccttccaa gccttgtttt catttcctcc 9660 tgtgaccgca ctgactttaccataaccaaa atacacattc acagaacaaa tgggtgtgaa 9720 attttgtcaa atgttctttctggattactt gatataatca tgagattttt cttcattagc 9780 ctattaatat gatggattacactgactggt ttttgaatac tgaaccatcc ttgtatctct 9840 ggaataaaca gcacttggtcatggtataaa atcatttttt aatatattcc tgaattctat 9900 ttgctgttat ttcgttaaaggtttttcttc ttttctactc ttattgtctg gttttgagat 9960 caggggaaca ctggtcttcatagagtgagt tgggaatttt gagtttttct atcttctgga 10020 agagattgtg tagaatttgtgttaattctt taaatgtttg gttgaattct ccagtgaagc 10080 catccaggac tagacatttgttttttgaaa acttataatc acaaattaaa tttccttaat 10140 agggttactg agttatttgcttcatactgg gtgagttgtg gtagtttata ctttgaatat 10200 cggtctattt catgtaagttatcaaattta tatatgtaga attctttgta gtattactta 10260 tttttacttt attatccttctggtatttgc agggtctaca gtgatatgct ctatatcatc 10320 tctgatatta acaatctgtcttctctcttt ataagctgtg taaatcttaa cagaggcttg 10380 tcaattctgt tgatcttctcaaagaaccca gctttcaatt tcatagattt tctttattgt 10440 ttttcttttt tgagtttcactgatttcagc tctttattat ttccttttgt tggcttacct 10500 ttgggtgatt ttactcttctttctctaggt tcttgaggag tgagcttcga ttattgattt 10560 gaaacttctc cttttctgctgtactcttta gtacatttta gtattagaaa tttccctgca 10620 ttgctttaac tgcatcctacaaattttgat atactgaatt tgttttaatt gagttcaatg 10680 cattttttaa attcccatgagatttgtttg atccatagat tatttagagg tgggctcttt 10740 cgttaacaag tccttggagattttacatta ttggctttac aaactttgtg gatttgggca 10800 aaatataaaa atgattttttaaaatgtttt gcaatatttt ggttaatgta aattttattt 10860 atgtagaata cttaatttttcttggctcat atcttgggct tacaccatgt agtatagtac 10920 ataatagctg ctcaatacaattctgttgaa taaatgaacg ttgtagaata ttaagcccat 10980 tcatttccat taaaaatttaatttttaaca tcttgctttg aatatttgat taaactcaaa 11040 atgtgaacca atattttcatataaaagatg aaatatgaag tgcatgatct gccttaaata 11100 ttccactaaa ggatgatacagttaattctg aattataaaa agtagattat ccgaagtttt 11160 ctttttctct tctgtgacagtaattaacaa aacaacaaac ctccatcatg gagtactgca 11220 agaggcaaga gattacatttttcttatttc tactactttt tgttgcctaa cacgtttagc 11280 tggtgggaca ggttctaagtatttgctaaa tattgttctc attattttga acatgtaaaa 11340 gatgactgca ttcttatatatttccctttt aagtttgaaa agtgaactac tttctttata 11400 taaaaattca tttgcctattgtctcagaat atcacatata actggtgcac tggacataag 11460 ggatacgggt tcccattgtggctttgtcta taaatagcta caaataaata gctataaata 11520 gttttgtcta taaatcttagagtgatgagt atcagttcaa catcagtaaa gtgagtggct 11580 tggagcagtc tcaggtctcctccatttttt ctgtatgact gtttcaatat tttctttttg 11640 actttcaatt gttgagtttttttcactctt attctaggta aagattcttt tcttgtatat 11700 cccgatcagg aatcatagcttctcaaatgt ttaccaattc tagaaaattc ttggccatcg 11760 ggcatggtgg cttatgcctgtaatcccagc actttgggga ggctgaggca ggcagatcac 11820 aaggtcaaga gattgagaccatcctggcca acatggtgaa accccacctc tactaaaaat 11880 atacaaatta gttgggcgtggtggcatgcg cctataatcc cagctactcg tgaggccgag 11940 gcaggagaat cgcttgaatccaggaggcag agtttgtagt gagccgagat tgagccactg 12000 cactccagcc tggagacagagtgagactct gtcccaaaaa aaaaagaaaa aaaaaaaaga 12060 aaaaaaaaaa ggaaaaaaaaattcttggcc attagctcct caaatattgc tcctctccca 12120 ttctgtctat tctcttccactgaaattttt gttagacata ttttggacct tctctttcta 12180 tctaccacta cctcttaccctctccttcac actcttaatc tctttatcat tctgtgtggg 12240 attctataga atttgcttagatctttacac ttactatctc tttagtctgt ttttaaaact 12300 gtccagtaag tttaatttcagtaattatac atttcatttc caggattcta tttagttgat 12360 tttaatatgt cttcactcttttcctctcaa ataacatatt ttttccctat gtttcttatt 12420 ctttcattta ttcctttaaccaaaactatc tatcaaagtt taactcaaca gcatttcttt 12480 tttcttggtg gtacatataacaacagtaat cttacaagga atgtcatctc tctttttttt 12540 aatgaagtac agtacttcagaataatctat tactcaaatt ttcagggaga gggtactaat 12600 attttcattt gttgtttctgttatcttatt atggtagatc actcccttat ataggtgttg 12660 tttttttttt aaatcattagttcattcagt taaggattaa cattttttcc ataatggatt 12720 tctacacaag ggtggtgcaaatttggattc taagtccatg tatagtgtaa gtttaggaaa 12780 atttctcctc tctgacactagaaccactgg gggaaacatt ctttgttgtg aaaggaatta 12840 ttcaattctt cttttcattcagggtacagt tcttcaatat ttctggttta gggttgggtt 12900 tcagctccaa attcctttttcaccactgcc caaggactca attatctctg tatagtgtta 12960 atacttgtgc ctctagaataaaaacattgt cttatttcta tctcttcttt tctgtgcaaa 13020 gcccagaata caaacgcttaaaacaatgaa taaactgcaa cttatttttc aaaagaatac 13080 atagctgagc ttgcaagaaccaaagcgaaa tccataagtt gtgaaaacac agagagaaat 13140 gaaagccaga acattatagcatcagctcag tcccaggttt tttgaaaggt gaggttctaa 13200 ttagctcaat ttatcacgccgctggaatta aagatttctc ttccacattt aacattctat 13260 gtttctggca ttttaaatgacatgaaaaaa gtcattttct gatatttatc tgttgatgaa 13320 atttctttat tttcatcattgtaagttaga acaaaaatta gcccggctaa tttttgtact 13380 tttagtagag acgggattttaccatgttgg tcaggctggt cttgaactcc tggcctcagg 13440 tgatccgcct gccttggcttcccaaagtgc tgggattaca ggtgtaagac accacgcccg 13500 acccctgaac tatataacatttaattactt tttaaaggga tgagaaatca ctctacatta 13560 aatttagatt gctatgattgcacgccaaaa taaatactta aatcatgttt acttagctct 13620 ttttaccatg tattccataaagattacaca ttggcataac ctaaatatat acaataatgt 13680 caccttacat ttgtacacagtgcttcacat ttaaaactat tttttgtttg cttttgagac 13740 tcagtctctt gctctgtcgcccaggctgga gtacggcagt gggatctcgg ctcactgcaa 13800 gctccacctc ccgggttcacgccattctcc tgcctcagcc tcccaagtag ctgggactac 13860 aggcacccgc ccacacgcctggctaatttt tttttttgta ttttaagtag agacgggatt 13920 tcaccgtgtt agccaggatggtctcgatct cctgacctcg tgatctgcct gcctcggcct 13980 cccaaagtgc tgggattactggcatgagcc accgtgccca gcctaaaaac tatttttata 14040 tattctcttt acatctccataatcctgtaa ggacgtaggc attattcttt ttttctagat 14100 aattgccata ataaattcatggaatcagtg tagggaagac aaaaaaagaa aaaaaaaatt 14160 cagatgagaa aactaagggacttgctcaaa gctgcacaac tagtaggaac agaataaccc 14220 aattcttaca gtgtcttcattcagggctcc ttccatttta ccacactatt caaaatttgg 14280 attctctatg tagccaaatggataatgaga acatgtataa aataataaag aaataaacta 14340 taatcataaa aagtaactaaaatagccaac tgtcatgtaa aaggtatgta gcaaactgac 14400 aggtaaagaa aatattttcaaaaatactta ctggatattc aaggagatct accggctgac 14460 ggaaaggctc tgaatcttcacattgaaata tgagatttaa caattcttca cactgtttct 14520 tccatgcttg aatatcgtaagactgggctc tattacgtaa tcttcttcta ggctgatggt 14580 cctgtgataa aagtgttcaaatatattaat aaaagagcac ttacacaata aaatttgtac 14640 ttttaatgta gtcttagataattgggtaat atacaataat tcaaacaaaa gaaaatattc 14700 accaagttct aaaaaacatacattttgtaa ttgaaactaa tttgaaatac ttaatgtctt 14760 ttaaaatgct aagagtaaaaaaataaagaa agctcttaat acattttaat tcatataaag 14820 tacttctgct aaaactaaaactatattacc ttcctttttc gagtagaagt tcctggcaca 14880 tcagcatctt tctcttcatcctttgaggca agaatttacc agattcataa aacattttag 14940 atgtcattat actttatagttgattaacta gcaattattt cctttacaca ctggaacacc 15000 tgtaatgtat atgctggggcactttattga ctcattaaaa aggttccccc cattaaaaaa 15060 ttttttttaa ctataagaagaatattctac tgccagttgt tttttttttt taaattaact 15120 acactagaca aaaaataatgttcacaacag cttttacctg aaaactacaa tatgtaaatt 15180 tttttatata gagaatatcaatatggtaat aataatgaaa tattacatac ctcagaatca 15240 gacaaaactt tcttcttcattgaattataa agtggaatta tgttataaca agtctgatcc 15300 ctacataaca aggaaatgttaacatgtaag attagaacca tgataatttt tttccttaaa 15360 aatttgttcg taaaaccatattttaaggta aaagttgaag ctgaaggctt gctttcttct 15420 ccattggctt actccaataatttatgcaca cacatttaac cctgacccct ccactctatg 15480 tagagctttc agtgtggcctcactatatca ttacaccaaa cccaagtctc atctcccagt 15540 ctttgcttag gtatctgctgtgcttcttcc attcctcagt cttcaaacag ctaatacatt 15600 tcttgtcttc caactctttcttttattttt aaatgtattt cctaaaattt tgttcttaac 15660 gcatcttgac actgtaccttttgcttcaca tacttgtggt ttatctgtgt aaatgaattc 15720 caaaattcct gcaatttgtcctaacccttc tcctgagcat tctaccaaca cctaaaattc 15780 cacgtctaaa cttaatagtgactccccaga tatccttgtt cctttttcta tttttcttta 15840 acaacatatc attcttacagtaatgggaat cttggttttt cattattctt tccctttcct 15900 cctccttata aacccaattagtggtcaagg gctgtgaact ctatcctcaa gtatgtctgg 15960 gcatctgtcc ctttctcactttcataaatt aagccctcat caactcttag ttggtcaact 16020 gtagcagtca atctgctatttatgcttttt gtctcttctc tgtcaattaa attagacact 16080 gcagtcaaat taacatttttaaggcatagt gtaaaacatg ttattctcat gttaatatac 16140 tttcaacagc cccttgctctcagagcttat attttagatt catattcaaa gccacccacg 16200 atgtggcccc aactcagatttatagcactg tatctctact gtgacttctc caatttatat 16260 tacccttaat taaaacttcctacctcacgc tgctccttat ccctggaatg gctttctttt 16320 catctaacat ttccagaatctatcagtatc tacaccttgt atacaatgtc ttaacagact 16380 tctcctcccc tgtatctgaatccccatcat cacagctaaa agtaatccta ttcttatcta 16440 aacttttata caattctcttactacttgtc acagttttcc ttatattata ctttcttaca 16500 gatttatcta tcctatgaaactgtattaaa aggatccatc acattacttt gtatgtatca 16560 attgcttgaa attttgccaaataactcaat taaaaagtat aataatcaaa atttcaagga 16620 atacttaata tcttgaagactatctgctaa aaaaagtatt tttaaacaaa ctatacacat 16680 ctaaaaaaat gccatggatttatttttaga aatatacaat acaaatgctt taagtatttc 16740 atgaatctga cttcaaagacatttcaaagt agccgtttga aagaaataca tttcacagac 16800 tttcaaatgt attaacaattttcatctaaa ttatttcact gaaatatgaa tatactatct 16860 catgtagttc tactgattctctttgaaaaa acagatacac atacacatag ttataacact 16920 tataaaaaat tacagacataagagtcttca gaggataatg cttaattact aatttcaata 16980 aggaaaacaa aagcatagcaataatagccc ccaaaccatt ggaaagcaat agatttctta 17040 gagaataagg tagagaaagggcacaaactt taccttatta attatgtttg gtgttttctt 17100 atactgaaat gacctgcattcctcagttaa aacacattaa tcaaaaagga gctcaaagat 17160 tatgtccatt aatgagaatgaagcagggat gtttattaaa aaaaaaaaaa aaactgaata 17220 atcctgaatt tttcattatgtaaaaatgaa agctgataac agctaagtaa gcttttaaaa 17280 tgctgttact acttctcaaccaggaaaaaa aaattcaata caaataatga catggaatca 17340 cagcagtctt tgtacaaaatatagaattca tttctctgcc ttcaacttag gaggctcaat 17400 tcattatatg attgcataaaatccttaaga taaggaaggg aaagtacttc tgccttaata 17460 aatagtgctt atcactcttgttatgggatc aatgaggaag taaacttgac tttgaagaag 17520 aatcatgaaa gttaaattcagtctcctgct ggactattta aatacttgtt aatatacttg 17580 acaggggcaa tatactgttaggatgaaaaa ttctcaaatc agatggcaga cactcattta 17640 ccgtgcaacc ttatacatgttaaccactat aggccacagt ttcctcaatt caaaattcca 17700 gataattatc tcttccacctgtaagattgt tatttgggtt agaagagtta atgtaggtaa 17760 aacattacat gttaaataaatttttactat tattattgtc taacagttag attgagaaaa 17820 taatcttttt ttaaacaattttaaccttaa aacacaatgg taatacgatt tttatgattt 17880 cattcttatt attagccaatgaactgtttc ttctgaaacc caggatcaaa ccagagacct 17940 ttagatcttc agtctaatgctctcccagct gagctatttt ggctactctt aaatgtttct 18000 tctttacaaa cagtatgttttctattttaa gaggaactgt agtgccatta attattaaaa 18060 ctatcataat tacatatgaaaagataactt actttataaa atgtagaaga agatcagtca 18120 cgaatttagc agatttcacaatagggcttc caggctcatt aaatgttcgt gtattatgct 18180 ctatatatcg aacttcccacattagggaag aaacccgcct taaaaaaaca aaatatagaa 18240 gttttaactt ccttatatttagaaatatgt gtacatcatt taaaaccaag acattccaac 18300 ttttcaactt cagtctaaaccaactgtaaa aaccattggt cttataaagt cattttcaaa 18360 gcagcataac tgcatttgtgttaggggaaa aaaagagggg caaccataac tacgtatttg 18420 catacaagat gtctggaatggaacacacca tattaacaaa ggcctctttt tgggagggag 18480 aacgtctata tggggagtggcaggagagta gaaaggggag agttttaagt tttggcttta 18540 tgtatttttg tcatgtgtgctgtcattttt tggtaataaa gaaccctcac ttctgaacaa 18600 aaaggaaaca agtaattttaatctaattat cttactggta atcaaatgac atatacaaat 18660 gagaagttaa ctgacagccaccttatgaga tacaaaatca taaaaatata gcatgctagt 18720 ttaccaagaa acctaactaaatgagaatta ttttctgaac acttaattga caatgctaaa 18780 ataaaatctg gagttttacaattttatttc tgaaagtaaa taaaaatcca aggacaactt 18840 ttgagaatat tatctaatatgtggcctgac ttaaaataat aaagaaaaca cttagaaaat 18900 cttactgatt gtgaacagaaatacaatcat atggaataac actgtatcta attgtggaca 18960 tagaaacata aagaaaaactgtgcatttca aatagattca caaggctcat tctgataaca 19020 gaatcacaga tatcttcagtgtatcatata gaaaactgtg tgtaaaataa agtattagat 19080 taataccagc agggcaaactgacagtaata gtttaacaag agattgaact agaagtttca 19140 cgaaagaaaa acaaactgtaagaagtctaa caccaatgag tgaaggaaga agcaaaaacc 19200 tacttacatt gtattgaatgtaatacattg aagtcatcat tgtattgaat aagaacataa 19260 cttaggttta taacagagtttattatcagg ttggaaaaca ggcaatttct aattcatgta 19320 agtattgtct ttcaaatgtttttttcctaa attggctaca aaactagggt aatgccaaaa 19380 gcctatttaa aatataatgtatcttgaaat acagatgttc ctcaactaac gatggtgtta 19440 catcctgata aacccactgtaaattcaaaa taccattaag tcaaaaatgc atgcgatata 19500 cttaacctag caaatattttacctcagcca agcctacctc aaatgtgctc agaacactga 19560 cattagccta tggttgggcaacatcatatg gcaatcaact gtacaataca ctgtacagta 19620 ttggtttaac ctcatgatcacgtggctgac tgggagctac tgggagctgt agctcactga 19680 catcgctcag catcatgaaagagtacatca caagcccaga aaaagatgaa aattcaaaat 19740 ttgaagtatg gtttctactgaattcatatc cctttcatat cactgtaaag ctgaaaaatc 19800 taagtcaaac cattgtaagtcaaaccttat gtatagtata ctttagcaat tatcatgttg 19860 agcaatatgt gagatatttacaacaatatt ggaagacatc agcagcttat atttctagtt 19920 gcagtccaac aattagtgtatgtatacaaa tagttctttc cttctcatcc acccatgtct 19980 tgtttcatct ctgaagcactaggtttaatt tccaatcttt agcaatttaa ggggtcaagg 20040 gagaaagagg aatatagttaggaattcctt tttttttttt ttttctctta aacttccaac 20100 acctgatatt gaaaaagacttgaagaatgc tttgagggtg ggatggttgg gaaccacata 20160 gcagggagga cttctccttatctctacgct ttttgacaaa tatcaaggaa gcaacagcaa 20220 gtacacctaa gaagatcagaaaaatcttta gaaactaaag tctaatatat tagttttctt 20280 tattccagtg gttctcaatcaaggacaatt atgctcccca gaagacatgt gacaatgtct 20340 gaacacattt ttggttttcacaactagggg gctgctactg gcatctagtg ggtacaggca 20400 caggatagcc cctcacaatgagatacagaa ataaaattta agtcataaaa agaaccaaag 20460 gcacatttta tatagaaaaatattaataca aaatatgaat aaagcttctc tatgttaaaa 20520 agaagaataa cggaaaggacttcagtaata aataactggt cacaaaaact tttaatgcaa 20580 tgttacacaa attaaattgttggactgcta agcaaaggtc atatgataaa aattaaaact 20640 aaaaacagga ttccattatttaaaaactat aaacatattt tttgacaaaa cattttaggt 20700 aataataaag cctactgacgattaaagaca ttcatcaaaa ttacctagat aatgcaaatt 20760 aattgaaatt atgcctgggccatttaactc taattctttt tcatgctaaa ctacaactat 20820 gaaaaactga gtattttcaaatttcagtgt tataagtaat gataagctga atacaggcaa 20880 aataagaaca aaatacataatacgaataca aaatttttat tatatattat attaaaaatc 20940 aatgaacaaa tattttaatgttatctagga gaaaatgaaa taccttgcct tgctttataa 21000 aatacaatat aaagacagtgaatatcaaat catgtcagcc tctaggaaaa actgtatcta 21060 ggatctagga attgtattttaagtgtctaa agaccagcag catcgacatt actgggactt 21120 gttagaaatg cagaatctcaggtcccactc caaatctact gaataagatt ctacatttta 21180 acataatccc cataatcttatgtgcattcc tatatacaaa aagttgagaa acactgctaa 21240 agatcagtaa atgggtggaaagatcaccag ctttcctttg atagtagcta catcaaatgg 21300 ttctaacctg taaaacctgttttccagtct ttgtttaatt gtacttagat ccgttggata 21360 tgccactact gtgcaatacatgggataggc ttgcagatcc acgggggcca caaatgctga 21420 ggcaatatct aaaataaatagataagtttg taaatttatt tttgtatgcc taaaataatt 21480 caagaagaat tctgcttgaattaagactta aaaagtccta atctacataa tcattagtct 21540 gccactgtct tttcataaacaatatagtgt agctgacata aagagtctca ctttttatta 21600 tgtctacatt tacactgccaaattctaggg gtattgtttt attcataggt tcaccgggag 21660 aaagaaacaa attatatatacatatatcag acctaataag tacacataca ttgccgtaat 21720 tgacagttgg ccattcctgaatctatattt ggcaaagcca ttctattatt aacactgtaa 21780 catactgcat tcaaatctaacctttgactt tctcaaacgt atccctttat ctcaacttta 21840 cattattctg tgaaatattagacaagtaga gaaaaggaaa cagacccaga agttttgatt 21900 cagtgatact gacccaatacacaccgtaaa gttgtacagc aaaaactata actagttaag 21960 atcactccca attttttgctcattcgcata taatacttaa tatcctaaaa tattgctaaa 22020 attatttaag gtagtatttataaggctatt cctataaagt gttggcattt tataaaatac 22080 ttcagatttg aatattcctcaatctccgtg tccatccagc tcttcttact catgttaatt 22140 tctctctaga ctctttgcagctgattcttt attgagagag tgggttgcta caaaccacca 22200 cataatctag ttacttcagaagcccagaat ttagataatc aagttttgtg gtcactgttt 22260 tcttttaaca aggcagagcaattaatatac cctctcctct ccccttaaga agatcctctt 22320 ttgtgtgtgt atattaagttgggggagacc agtacaagct acccatataa ttataactca 22380 gctttcaatc ctcctcctccaattcatatc atgtcagcct gaatatgtca agtgttttaa 22440 attgggttgt ggaggacccagttttttcag agatgcctct ggcacttcta ggaggccctt 22500 attctaaaat tcagctaacataacctaatt tataactgtt ttaaatagtt aagtcctgtg 22560 ttaagaccac attcaaaaagagattccact taaaatgtct gaaaccactg acttaggata 22620 ttgtgaaaaa aaatttttgttggagaataa cagtattttt ccattacttt gtgttctgcc 22680 agttttttct atactcgcgtgttgctttac ttacctagtg tcatcaactg gtttattcct 22740 gccacaattc tttcacattcttcatccctg ggattggtac cccattctcc atcaagaggt 22800 ttatagatta gtgatctgcactcaccatca gttaaaggaa cactggtacc tagttcttca 22860 ggaaatacag ctgaaatagaaaagcagatc attgcaaata catggtaact tattagtatt 22920 caggttagct ttagaatgtaaaaataacag tcacaaaatt aaagtatatt ttgtatagat 22980 ttgtaaatat actctttattttaacaaagg aaagtatgtt ttaagggtca ctaaaattta 23040 aattaatttt taaatgatactataagtaat tctctaaata attacttctc caaaattata 23100 cctgaaaatc tgctctgtaatcaagtacat gtgcagaaat catttctata aaatatgcaa 23160 atttcaaagt tttctgaatcacttcataat tgccatgttt actttgataa agtatacaca 23220 aggtaaaact gaactaaagtgacattttct agaaatactt caatcaaagc ttcaattttt 23280 gaatgtagga acagagagaattatgaaaac tgacaaatga tgcttatgct tattactcat 23340 aaattatgaa ggtatgctttctgcatgctt gaatctttaa cagttttagc tgagagaatc 23400 actagagggt tgcggtaacccaaaatctag aaacgtgcta ggtaattttt cctttagact 23460 aagttttggc agatacactctagaaaatac gccactgttt gtgtacaatc aaaattctca 23520 tcacaaacta cgattaaactctataggttc gtatgaatgt gtatccaaat agaacaacaa 23580 cagtaaccac ccttcaatatatttaggtag gaaacaaaac agtgaatcag tatcacttat 23640 tcatttaaaa aatatccaaggcattataac accaactggc tgcattgcta tcatattcac 23700 aacagttcaa tgtgagttcaaattcaaact ttctttttaa taaatgagag aaacaaaaca 23760 aaaacataag ccatgtaacatggttaccaa ttgatttaag atattttata attttaaaca 23820 gctctaattt agcagtgagataaaaaaaaa tatattattg gcattaaatt ttcaaagtga 23880 taattcctgc agagaactaatcttagctaa tcagtatgac aattttctca tttctgaggt 23940 ctacgagact gggttattttctccaacagt tattttttct ctgactttgg attacaataa 24000 ctactgagca actcaattaataaaagatta tttctactat gttagaaatt agatgttttc 24060 ctttttgttt tttaaagatcttatttattt ttatctgcta agagatgtaa tatattatta 24120 ttatttttga gatggagtctcgctctgttg cccaggctgg agcgcagtgg tgcaatctcg 24180 gctcactgcc acctccgcctcccaggttca agtaattttc ctgcctcaac cttctgagta 24240 gctgggacta caggcacacgccaccacgcc aggctaattt ttgtattttt agttgagacg 24300 gggtttcacc atgttggtcaggctgctctc caacacctga cctcgtgatc cacctgcctc 24360 agcctctcaa agtgctgggattacaggtgt gagccaccac tcctgccctg taatatatta 24420 ttttttaaaa atcaaacaatatagaataac gtaaaagaat ttatgaagtc tttataatgc 24480 tactctataa ataatcattattaaaatctc gacaatatcc ttctaatccc tttttggctt 24540 atgcaattgt gcatgtgtgttgtatttttt acaaacaaac aaaaatgggc aatgaagtgg 24600 aaagaaaata taatctccaggctttggtcc caacgtcctt ttctcagtgc aaggaagatg 24660 tcatactcac tgcctaaggctaattattaa atcctgaatg tgtcaggcca tatgcataat 24720 gacagttata ttatcattattaattacaac tatatcttca ttgagctctt atatgtgtca 24780 ggctctacaa taagcactttacacacatga tgctatttaa tcttcaaagt agccctataa 24840 ggaaggtatt agctttgacggtttctaagg ccgagtacta aaaagttggg gtgtgaggct 24900 ttatggaact tgccaagatcacataaaaaa tgacaagtca ggatatgaac tgatgtccgt 24960 ctcactcaaa agcatgacctcttaactatt atgttacact ttaaacactc tgctaaagtt 25020 acaaaagtgt ctctgcctcccaaatgcaca ctttcttggg tgaatagtaa ttaataaaac 25080 aatttcatgt tttgctgtaataaattaatt tcaatcaatt ccaagtaggc aagagttata 25140 tctatcttct tcactgctgaatctccccta cttcaaggtg tacaataata aatatttgcc 25200 aaatgaatgt tttctatttgatactcacaa ctgtaagtgg tagcatgtta gcaaatctta 25260 aataatttct taagaaattaactccataat ggagaaacaa aaagcctaac acacacttac 25320 cattattagg tataagctccatatcccaag gactcatctt ttctgtatct ccattgtccc 25380 agcttaaaga aagaaaaatcattatattaa aaaatctaaa ttattgtatc acaattttaa 25440 taaaatcaat tatcaaaataattgcttctg tgtttaaaag aagtctcttt atctcttaat 25500 agatggaaaa aaaaattcaaagcaagccta ggtgaactaa aatacaacaa atatttcctt 25560 accaaacatt gtagcattgaaacagactat cagggtactc aagttgaaga ggttcctggc 25620 tttcgattgt tccaaaccaccaggcatcat ctatgacaga cctgaagcgg tcacctggcc 25680 aagaacaaaa actaactcatcattctgaaa tgcatggctg ctgtcactgc tttttcctaa 25740 cgttaacctt taagtacctaaactgcctgt atgatttcag aagacaaaaa gtgaaccaca 25800 aactccaaaa ataagtaagtacaatcagca ataccaagag aaaaaaggaa tttagtaagc 25860 atacttgaag tgtgacttaacagttttcaa ttctattttt tatatttcat taaggtatac 25920 agaaattcac ttgttttaggcatttttacc aatctagcat ttgaaattca tcattaacac 25980 tatacccaaa cttttcactgaaataaaatt ataattgcgg caagttccac tcaacaatta 26040 cttagtcttt taatttcttactttctgtaa gcaagtttcc ccaaccaaca atcaatcaag 26100 actccacgct aaaaacaacaaacaacataa aatccaacct gtcttccttc atctcaatca 26160 cccttaatac tcactcactctccctttcct gtaaaaggaa acaaaaaaga aacaaaaata 26220 aaacaactat tctttttaaaacagaggaca ctccttgtgt ctatttcctt atccaattgc 26280 tgtcgtcgta ttacttaacctgctttttcc caaagacctg aacaagctat aaatgctatg 26340 gctttttctt atctaaatattctcatgttc cttctgtgtc ataagaaaac tgtaagtcac 26400 ttacttcctt tatgcaatgttttcctgttc ctcagctatc acagtacttg agttttctcg 26460 tggctagcat aggctagagcctgaaagact tgggttcaaa taacgtatct gtataacttt 26520 gaatatatta attatttttgaacttcattt tccttgtcta taaaatagaa atggtgatgt 26580 ctacctcctg gtagtttttgactaatgagt tctattaaag cactccacat tttgacacac 26640 agttaagtta aaatgaattaagttagcaat taatctgaat cagttttatt tttaaactca 26700 aagagaaaag tagttatgttctcattttct taccaaaaag gatttaaaag tttataaaaa 26760 catatagcat gaaatgaattaaaaattaga aaaacaaggt aaaagaatat gataaaaaag 26820 aaaattggag ccaggagaaaagttaataga acacaactgc atgctgttga cagttgttcc 26880 tcagatgcat actagtgacacttaacaaaa agctactata tagtttaata agaagcattc 26940 ttgacaccac cactacctcacactaaacat aaagtttcaa agagctgtat cttatgaccc 27000 tacacagact gattattatgctaaagagga aggactgagt aatgtgtgcc taatcataac 27060 gaacaatatc tgtagaataacaagaaagtt aagcaaagaa cctggactac tactgaagtc 27120 caccattgag agtaagccttaatacatttc cgaggagggg ctgaagtaaa aattactaat 27180 gtaattttaa atggcagtcggtgggtgaat gcatatatcc tcagatataa aagattaatt 27240 agatactaac tttagagaaatattaaccca taaattagaa taaaattgta agatccaaat 27300 gagaaaatta tgatgctcattcattttaat tctctgtgat ttgtccaatg ttagccacat 27360 tactttgcca aggttatgagctcacttctg gaatattgct gcactttgat ctctattatt 27420 tgttccgcaa tttattggcaaatgcaactc cttaaaaaat aaaatttatc ggccgggcgc 27480 ggtggctcat gcctgtaatcctagcacttt gggaggctga ggcgggcgga tcacaaggtc 27540 aggagatcaa gaccatcctggctaacgcgg tgaaaccctg tctctactaa aaatacaaaa 27600 aaaaaattag ccaggcgtggtggcaggagc ctgtagtccc agctaatcgg gaggctgagg 27660 tagaatggtg tgaacctgggaggtggaact tgcagtgagc caagatcacg gcactgcact 27720 ccagcctggg tgacagagcgagactccatc tcaaaaataa aataaaatac aatttatcat 27780 atcaagtaat gtatgtgaaaaatttaaaca atcagatgta ccaaaggctg atagccaaaa 27840 ccaagaaaaa tgttttcatctattttacct actacttctt gacttacaga tttcttcact 27900 catcaatttt tgacagtaagtatcagagtt gattcttgaa gacatgggtt ttaactgacc 27960 aggtctactt atacacagatttttccaata aacagatttg gccctctgta ttggcagatt 28020 ctgcatcagc aaccaaatgcagattgaaaa tacagtatta gtgggatgtg aaatccatga 28080 atatggaagg gccaacttttcacatcgggg ggttccgtag gatcaattct ggaacctatg 28140 tatgcaaaga ttttggtatccatggaggtc ctggaagtaa ttccctgtgg atactaaggg 28200 acaactataa cttcaatacaactgtgcata aaaagtatgt gtattatatt taatccatat 28260 tcaattttta atcatgactgtgtaaatact gcttgctcct aagcaaaaca gcatataatt 28320 ccttccttat ataattttgttttccctaaa attaataatt gcttcatttt tttaatgctt 28380 ggttttcagt gaatttacaattaaatcttc ccacaatctc taacagctca agctgtaaaa 28440 aacattcttc aatgtaattttccacaaaga caaacttgtt agataagtta tgtgttccaa 28500 ttttttcccc ctgaagactttcctcttgaa ggagatttgg acctgctagg tagctgctat 28560 cctgaggctt ctactgaatattatttggga ttccttttaa cttttcctgt tctggacttc 28620 ctgtttcctg aggggattccattcttttcc ctttcttggt tactccctta tttgatgaaa 28680 cacatctttc aaaacttctagggaaatgga acatgagatg taaattttct ttctaacttc 28740 catgtccata attttgatagcttccaaatt ttcctaattt ctccttacag agcacataca 28800 agtttttaac aaaggacaaaccaccatgtc aatgcgttct agtggcactg aaggacagac 28860 tggtatatca attgatgtgctttttcaaac catacatacc gtgtacacat cataccatga 28920 cacacactgg tcctatatgaaatttttaag agaactactc tcataagtgg cacatcatct 28980 atatgtaaat taatgcaccttaagtgcctg aaaactttta cagattttag tttctttgag 29040 acttgtttat gatactaattttaaagatta taataggatt aaccaataaa agaaaaatgt 29100 cagtttagct ttagtcccagtacaaactta tacatcttgt taagcttctt ttggcttcaa 29160 atttaaattg ttattaatatttttatacaa aaatttaact taacatgtaa aacatgaaaa 29220 taaagtcaaa tgtaacagaaaaaatgtttt aaatttcaac atcgactgtt ttcattccta 29280 aacaaaactt aacaatacctctgacatagt atcttacttt gctattaaca ttcctacaaa 29340 tagcaaaaag atttctctgataatcttttt ctcaattatg aaaaatagta aatcacttac 29400 taagaaaaaa aaaccacatcaaacatcgat agcttctaaa taaattaccc acctatattc 29460 catcgcctgt attttgcatcatcaaattgt tgtctcaaga ctaggaaatc tataacgtca 29520 ggcatatcat ggtatctaattacaaacaga aacaaattga ttaggtcaca tacctaaaaa 29580 tacctaaaag atgttcaaatgtatctgaat cttgaaaaac aatctacaat actaagaaaa 29640 ccattgcctc tttcaacagtccttacttca tggtaaatga tccgccagtc agtttaccag 29700 tatcaggatc tagaaaagcaagtttaaggc agcaaagggt aggtaatccc acttcatact 29760 ttatgccaac tattttcataagttcttgtt cctgagagag acagagaata taaggaacca 29820 tctttacaaa ataaaccacaaaatagactg ctaaacattg ttgagaaaaa acttcttggt 29880 ttaaatcttg atctggatggtgatgactgt gtacatgtaa aaattcactg agctctgtat 29940 taagatttgt gcactttatagtatgcaagt tacaatgaaa tttttaaaac gtaaaaaagg 30000 aaaaaaaaat aaggagaactttactaaagt atagttacta aagtaagttt tctatcacca 30060 ttccaaagac ctattggtaactgaactact gatgacaaat ctagaaatac gcatcaaatt 30120 tacgaataca aagcttactttagacttatt acctaatttt cactataact aaattttgta 30180 cccaacccat aaactgcattggagtatata aattcagtca aatcttgtgt ttctctggat 30240 gaaaattaaa cacctcctactctctaggac tgcttcaatt aaacaaggta tcttcatgat 30300 gcagtttctt attgtgttaatagtaacctt tgatacaatt ttctccaaat tccataattg 30360 tatttttggg gctattaaataataaatcaa tgtcataccc gtagctccat tttatgccat 30420 ggttgttttt tgggattgatactatatatt ttatttttcc gggccatttc gacataggct 30480 tcatgtcctt gtcggaaataataaacctaa aaaataaagt cataatctta caacctggat 30540 gtgtttcctt taatccaatatacagggtat cagctgaaat tgcaaagaga aaatctaatg 30600 ccttttcagc taatagaaattctaatattt tctccctcct cctttctctc aagttgtctt 30660 aacatcacta aatcataaccaaagtgttct aaataacatt actttgaata cacacttata 30720 agttaagatg aaaagttattttctggtttc accattttat tcttaaaatc aaaataagtt 30780 aatctatgtt gcataataacgttgactaat aagtttattg tccacttttg ttgttaactt 30840 ttttagcaag tagtttgtacatatgcagaa aacattgaaa tgaaaaatgt actttcacat 30900 atattttaat ccttacacaaatcctggtaa gacagcaggg catacattta tccacatttc 30960 atgaagatca aatttaagtgactcctgact actgtcttgg agaactagta cttgaacaca 31020 gcagtctgac acccactagtagaagaacgt gttttaaaat gctaagtttt tagtaacatt 31080 ttgggatagc cactatcccatactttcatt ctattcatta ataccattat tgcggggagg 31140 ggccaagatg gccgaataggaacagctccg gtctacagct cccagcctga acgatgcaga 31200 agacgggtga tttctgcatttccatctgag gtaacgggtt catctcacta gggagtgcca 31260 gacagtgggc gcaggtcagtgggtgcgcgc accgtgtgcg agccgaagta gggtgaggca 31320 ttgcctcact caggaagcacagggagtcag ggagttccct ttcctaatca aagaaagggg 31380 tgacggacgg cacctggaaaatcgggtcac tcccacccga atactgcgct tttccaatgg 31440 gcttaaaaaa cggcgcaccacgaaattata tcccgcacct ggctcggagg gtcctacccc 31500 acggagtctc gctgattgctagcacagcag tctgaggtca aactgcaagg cggcagcgag 31560 gctgggggag gggcgcccaccattgcccag gcttgcttag gtaaacaaag cagccgggaa 31620 gctcgaactg ggtggagcccaccacagctc aaggaggcct gcctgcctct gtaggctcca 31680 cctctggggg cagggcacagacaaacaaaa agacagcagt aacctctgca gacttaaatg 31740 tccctgtctg acagctttgaagagagcagt ggttctccca gtacgcagct ggagatatga 31800 gaacgggcag actgcctcctcaagtgggtc cctgacccct gacccctgag cagcctaact 31860 gggaggcacc ctccagcaggggcacactga cacctcacac tgcagggtac tccaacagac 31920 ctgcagctga gggtcctgtctgttagaagg aaaactaaca aacagaaagg acatccacat 31980 caaaaaccca tctgtacatcaccatcatca aagacaaaaa gtagataaaa ccacaaagat 32040 ggggaaaaaa cagaacagaaaaactggaaa ctctaaaaat cagagcacct ctcctcctcc 32100 aaaggaacac agctcctcaccagcaatgga acaaagctgg acgcagaatg actttgatga 32160 gctgagagaa gaaggcttcagacgatcaaa ttactctgag ctacaggagg acattcaaac 32220 caaaggcaaa gaagttgaaaactttgaaaa aaatttagaa gaatgtgtaa ctagaataat 32280 caatacagag aagtgcttaaaggagctgat agagctgaaa accaaggctc gagaactatg 32340 tgaagaatgc agaagcctcaggagccgatg cgatgaactg gaagaaaggg tatcagcaat 32400 ggaagatgaa atgaatgaaatgaagcgaga agggaagttt agagaaaaaa acaataaaaa 32460 gaaatgagca aagcctccaagaaatatagg actatgtgaa aagaccaaat ctacgtctga 32520 ttggtgtacc tgaaagtgatggggagaatg gaaccaagtt ggaaaacact gcaggatatt 32580 atccacgaga atttccccaatctagcaagg caggccaacg ttgagattca ggaaatacag 32640 agaacgccat aaagatactcctcgagaaga gcaactccaa gacacataat tgtcagattc 32700 accaaagttg aaatgaaggaaaaaatgtta agggcagcca gagagaaagg tcgggttacg 32760 ctcaaaggga agcccattagactaacagcg gatctctcag cagaaactct acaagccaga 32820 agagagtggg ggccaatattcaacattctt aaagaaaaga attttcaacc cagaatttca 32880 tatccagcca aagtaagcttcataagtgaa ggagaaataa aatactttac agacaagcaa 32940 atgctgagag attttgtcaccaccaggcct gccctacaag agctcctgaa ggaagcgcta 33000 aacatggaaa ggaacaaccggtaccagccg ctgcaaaaac atgccaaatt gtaaagacca 33060 tcgagactag gaagaaactgcatcaactaa tgagcaaaat aaccagctaa catcataatg 33120 acaggatcaa attcacacataacaatatta actttaaatg tcaatgggct aaattctcca 33180 attaaaagac acagactggcaaattggata aacagtcaag acccatcagt gtgctgtatt 33240 caggaaaccc atctcacctgcagagacaca cataggctca aaataaaagg atggaggaag 33300 atgtaccaag caaatggaaaacaaaaaaag acaggggttg caatcctagt ctgataaaac 33360 agactttaaa ccaacaaagatcaaaagaga caaagaaggc cattacataa tggtaaaggg 33420 gtcaattcaa caagaagagctaactatcct aaatatatat gcacccaata caggagcacc 33480 cagattcata aagcaagtcttgagtgacct acaaagagac ttagactccc acacattaat 33540 aatgggagac tttaacaccccactgtcaac attagacaga tcaacgagac agaaagttaa 33600 caaggatacc caggaattgaactcagctct gcaccaagca gacctaatag acttctgcag 33660 aactctccac ctcaaatcaacagaatatac atttttttca gcaccacacc acacctattc 33720 caaaattgac cacatagttggaagtaaagc tctcctcagc aaatgtaaaa gaacagaaat 33780 tataacaaac tgtctctcagaccacagtgc aatcaaacta gaactcagga ttaagaaact 33840 cactcaaaac cactcaactacatggaaact gaacaacctg ctcctgaatg actactgggt 33900 acataatgaa atgaaggcagaaataaagat gttctttgaa accaacgaga acaaagacac 33960 aacataccag aatctctgggacgcattcaa agcagtgtgt agagggaaat ttatagcact 34020 aaatgcccac aagagtaagcaggaaagatc caaaattgac accctaacat cacaattaaa 34080 agaactagaa aagcaagagcaaacacattc aaaagctagc agaaggcaag aaataactaa 34140 gatcagagca gaactgaaggaaatagagac acaaaaaacc cttcaaaaaa ttaatgaatc 34200 caggagctgg ttttttgaaagatcaacaaa atcgatagac cgccagcaag actaataaaa 34260 gaaaaaaaga agaatcaaatagatgcaata aaaaatgata aaggggatat caccaccgat 34320 cccacagaaa tacaaactaccatcagagaa tactacaaac acttctacgc aaataaacta 34380 gaaaatctag aagaaatggataaattcctt gacacataca ctctcccaag actaaaccag 34440 gaagaagttg aatctctgaatagaccaata acaagatctg aaattgtggc aataatcaac 34500 agcttaccaa ccaaaaagagtccaggatca gatggattca cagccgaatt ctaccagagg 34560 tacaaggagg aactggtaccattccttctg aaactattcc aatcaataga aaaagaggga 34620 atccccccta actcattttatgaggccagc atcattctga taccaaagct gggcagagac 34680 acaaccaaaa aagataattttagaccaata tccttgatga acattgatgc aaaaatcctc 34740 aataaaatac tggcaaaccgaatccagcag cacatcaaaa agcttatcca ccatgaacaa 34800 gtgggcttca tccctgggatgcaaggctgg ttcaatatac gcaaatcaat aaatgtaatc 34860 cagcatataa acagagccaaagacaaaaac cacatgatta tctcaataga tgcagaaaag 34920 gcctttgaca aaaatcaacaacctttcatg ctaaaaactc tcaataaatt aggtattgat 34980 gggacatatt tcaaaataatcagagctatc tatgacaaac ccacagccaa tatcatactg 35040 aatgggcaaa aactggaagcattccctttg aaaactggca caagacaggg atgctctctc 35100 tcaccactcc tattcaacatagtgatggaa gttctggcca gggcaattag gcaggagaag 35160 gaaagaaagg gtattcaattaggaaaagag gaagtcaaat tgtccctgtt tgcagatgac 35220 atgattgtgt atctagaaaaccccactgtc tcagcccaaa atctccttaa gctgataagc 35280 aacttcagca aagtctcaggatacaaaatc aatgtgcaaa aatcacaagc attcctatac 35340 accaacaacg gacaaacagagagccaaatc atgagtgaac tcccattcac aattgcttca 35400 aagagaataa aatacctaggaatccaactt acaagggatg tgaaggacct cttcaaggag 35460 aactacaaac cactgctcaaggaaataaaa gaggatacaa acaaatggaa gaacattcca 35520 tgctcatggg taggaagaatcaatattgtg aaaatggcca tactgcccaa agtaatttac 35580 agattcaatg ccatccccatcaagctacca atgcctttct tcacagaatt ggaaaaaact 35640 actttaaagt tcatatggaaccaaaaaagg gcccgcattg ccaagtcaat cctaagcaaa 35700 aagaacaaag ctggaggcatcacactacct gacttcaaac tatactacaa ggctacagta 35760 accaaaacag catggtactggtaccaaaac agagatatag accaatggaa cagaacagag 35820 ccctcagaaa taacgccgcatatctacaac catctgatct ttgacaaacc tgagaaaaac 35880 aagcaatggg aaaaggattccctatttaat aaatggtgct gggaaaactg gctagccata 35940 tgtagaaagc tgaaactggatcccttcctt acaccttata caaaaattaa ttcaagatgg 36000 attaaagact taaacgttagacctaaaacc ataaaaaccc tagaagaaaa cctaggcatt 36060 accattcagg acataggcatgggcaaggac ttcatgtcta aaacaacaaa agcaatggca 36120 accaaagcca aaattgacaaatgggatcta attaaactaa agagcttctg cacagcaaaa 36180 gaaactacca tcagagtgaacaggcaacct acaaaatggg agaaaatttt cgcaatctac 36240 tcatctgaca aagggctaatatccagaatc tacaatgaac tcaaacaaat ttacaagaaa 36300 aaaacaaaca accacatcaaaaagtgggcg aaggacatga acagacactt ctcaaaagaa 36360 gacatttatg cagccaaaaaacacatgaaa aaatgctcac catcactgcc catcagagaa 36420 atgcaaatca aaaccacaatgagataccat ctcacaccag ttagaatggc aatcattaaa 36480 aagtcaggaa acaacaggtgctggagagga tgtggagaaa taggaacact tttacactgt 36540 tggtgggact gtaaactaattcaaccattg tggaagtcag tgtggcgatt cctcagggat 36600 ctagaactag aaataccatttgacccagcc atcccattac tgggtatata cccaaaggac 36660 tataaatcat gctgctataaagacacatgc acacgtatgt ttattgtggc attattcaca 36720 atagcaaaga cttggaaccaacccaaatgt ccaacaatga tagactggat taagaaaatg 36780 tggcacatat acaccatggaatactatgca gctataaaaa atgatgagtt catgtccttt 36840 gtagggacat ggatgaaattggaaaccatc attctcagta aactattgca agaacaaaaa 36900 accaaacacc gcatattctcactcataggt gggaattgaa caatgagatc acatggacac 36960 aggaagggga acatcacactctggggactg ttgtggggtg ggggacgggg gagggatagc 37020 attgggagat atacctaatgctagatgacg agttagtggg tgcagcacac cagcatggca 37080 catgtatacg tatgtaactaacctgcacaa tgtacacatg taccctaaaa cttaaattaa 37140 aaaaatacca ttattgctccagttgtctgg aactttaaat gatggaatag tgctgaataa 37200 tgaagacctt caagcaccagcagctaaaaa gacaacctaa ccattttgaa aggaaatcat 37260 tcaacaagga attacaaacttttctggcca tgttgaaata atgtattaaa tataatttca 37320 catcttaatg ctacaggatgttaagatcta tcactgtact atatcacaac aatgtggtaa 37380 tgttctgtgc tcttcaagtcgtatgaggca agtaggattt ttaaataaat tctttcagac 37440 tgttctttag aatcactctagcattaaaaa gtttttgttt tctttttttt cttaaagtgt 37500 caattaccac tttatactgtaaattagtgt gctttgctaa agaagcctct attttaattc 37560 ccaatttatt tatggtcaatctgttggaca ccagataaca ctgcctctta aaatttgtgt 37620 acaaaacaag gagacattaaccttgagtaa aaaatgttga gaccagttct tacattttca 37680 ttctaaattc acaagtacatattctaaaac aatggtctca tcctcagttt cttaaaaatt 37740 aaatagtatt tcttattctaagattataga ttttttaaag atctaatgaa ctgtgaacac 37800 tgtgggtaaa caaaacactaacactttttg aaataaaatt aaatgaaaac aaattgctaa 37860 atttcatttt tcctttaacatgttatacat taagccttaa gataaatgaa tatattttaa 37920 tttaaaaaga aaaagaaagctggcaataaa aacctcttac taaaacatac atttcttttt 37980 aaaacactaa caaaattttcattcttataa tattcagatt tacagcagct tcaaagaaga 38040 ttattagact ttcactcctaattgtacttt ctccatacat agatacaaat atctagaatg 38100 agatacttta caaaactgcttctattttcc agaagtctat ttcaagagct gttaaaaaat 38160 gtttaaaact atgtgaggaaaaatggataa tttaaaactt ttaaagtacc tcatcaccca 38220 tctgtggcac aaatggacatcttcggggaa tggtatctgt aatccatgtt gatggcaacc 38280 attcttctaa tgtcaaaccattttcagtta gttctcccac agccaatctc tgacaaaatt 38340 taagtaataa ttgttaagtaataatcaaaa aagcattaat ccacaaatct actctttaaa 38400 ataactataa agataattaaataaaagggg aagggcacca ttgtacaata ttatatacag 38460 ttggccctgt gtatccatgggttccacatc catgcattca accaaccttg actgaaaata 38520 tttggaaaaa aaattccacaaagttccaac aggcaaaact tgaatttgct acattctgaa 38580 tactatgttg aatccacacaaataaaatga tgtgtaggca ctgtagtagg tattataaat 38640 aatctagaaa tgacttaaagtatataggag actgtgtgta ggtcacatgc aaatactata 38700 tgccattttt tataagagacttgaacatcc ctggattttg ttatctgcag gggtcttggg 38760 accaatcctc cgtgtctactgagagatgac tatcctttaa gcaacaaaac acttattcta 38820 gaaaaaatgg cagcagtggcaacagagtta ttcaatctct ccaaatcact gtctacaaag 38880 agaactaact agaagcaaaacccaaaaatc catagccaac actcacaaca aggtaacaag 38940 atatccccac aaaccccaaagtacaagctc tgtgtattct cctttccttt caaaatgcta 39000 tcaattttat aaacattccatataacaaac caagacagcc tagagttttt ttttaatcct 39060 agttatagta agttacaactaaataaggta ttctcatagg agttgagtag tgcaacatgt 39120 agaaagctaa ttatttccataagctggaca ttacacttct acacagcatg agaaactatg 39180 cctctgagaa agttccttaactttgctggt cacccacaag tggccacaat ggtcttgatg 39240 ttgttacctt agactcaggaaaaaaatgaa ctttctaaga acatttgaaa cctaatattt 39300 ttacaagtaa aaaaagttatgcaattgatt aaagtctttt gtgaatcaca cgtaaaacat 39360 taaaaatgat tgtacactaagactgctaca ttttacttgt ttttttaaaa acaaggtagt 39420 gtaattatca gtataaaataatacttgttt actaaaagaa gcaatgccat aacatgatat 39480 cagagaacac tacttgcaataggtaatact actacttccc aactgtagta gttgtcattt 39540 tcctcttttt cctattagccacagccacac tgagtgtttc tcagtcaaac atatcaagag 39600 cattaccctg gagagttagggtaaaggtct ttggaattta ctgtacgtga gatgggctcg 39660 ttacagaatt ttaggcagaagcatagtacg atctcactta tattttaaaa ggatcactct 39720 ggatgcatca aaacaaggatcagcaaatca tgaccctcag ggcaagtctg gcctgccaca 39780 attttcataa atttttatcggaacacagcc atacccattt atgtattgtc tataaatgct 39840 attatggcag agtagctggccttctgtaga aaaaatctgt caacctatgc tttaaagaat 39900 agaccctagg gagaaacaaggagaaacagg aagacacatg agatgctacc acagtaatat 39960 aaatgagagt tcagggtgattcacaccaat gtgatggcag tggagtggtg aaaaacagta 40020 aagtgctgaa tatacttataatccattaga taattaattc cctgatggac tggatgtgga 40080 atatgagaga aaaagaggaatcaaagatat ctccagggtt tctggtataa acaactaaga 40140 gagtcgtcat attactgagataaagagggc tggggtacag cgggtttgag gaaaaagctt 40200 ggtaaataag ttttgtaggtgttggatgtg aggagtaaaa tgatatccaa acagtaattt 40260 gatatataca cagttatcaaataaagtagc cattatgtta tgcactgagt atatcacaga 40320 gatcccacaa cccaggaacttccactgtgc tttattcaga gcagctgcta tcagttttgt 40380 atactgagga gctaaaagtttgtttgaaaa aggtttcctt tgactaataa aaaggaaaag 40440 aaagacagaa aagtttgaaaatcataattc tagcctcaat atggactatt aattgctagg 40500 caaggatttc tccccataaggaatttatct atgttcaatg gggaagctaa caacttttac 40560 atcaagacag gtaagttgtatattaaataa gaataatcat atgtatgact gaaagacttt 40620 gggcatcacc aaaaatcattatgaggacat atcttattcc ccaataattc ctgaggaact 40680 tagaatgttt ggttgaggaagatttctgtc acttattaat tataaccatt aaggggttaa 40740 gaatgcattg agtattctttaacatttcta gctccatgat ttgaggtttt tttaaatatg 40800 gaaagtataa ataatttctttcctttccaa ccatgggaat gcttctaggc gcagctcaaa 40860 tcttatttcc tctaggaaatctcatctgaa atcccaacat aagatgaccc tgtttaagaa 40920 tggaaatact tttatgtttatttgagataa ctagaggact agggaataag aacaagtcca 40980 tctactgtta catcactgctaggcatgcga acaaaattta aactaaaggg aataccctcc 41040 agtatcctaa ccttaccatatttaaagtga cccacataat tctattggca gagtcatcct 41100 atcacaatac tttgttgcaacaacacagtg aaattaaaac ctgccaaatg ttaacaatag 41160 atctatatgt gccagtgcatgaaggagccc atggtattag tttgaggaaa attatcaaat 41220 taaggggacc agatgaagcaaactgtactc ttgggatgaa ggaactgttc tcacagtaac 41280 ttatcactgc aaacctcaaaagttcatcaa aactgtcctg agatgaaaaa gaatatttac 41340 ctaattagcc agacacatggctaaatcagt tttctttaac caatctgtct actacataca 41400 taaaataaca aatcagactacatttatcat cactgacaag gtagaaaaga aaatgtgtgg 41460 gtaaatgtgt ggcattctctttggtaaagc ttccccaaac aaaagcaaag gagacaacaa 41520 gaaaaacagc agctgtggaatccaaattaa agtaactcat aattataaag ctgaaacaag 41580 aactcaacaa atgtagataaaataaacact taaaacagat atattcttat actttttgaa 41640 agctctgtgg gaataaagaccctacggtct cctactattt aattctacaa acgacaattt 41700 atacttaaat ggcagaggttacaaaaaaat cttcctttta accaaatact gcttcccatt 41760 tacagtcttt tgggaagcagaaaacatgcc cctcgtgttg tatttacttt agaacaaaaa 41820 ttaaacaggt ctcattttcattcctatgtt aaagaatttc aactccataa gagctgacag 41880 atattcttcc tataatatttcttacgttct ctgctttctc tcaaattgtc cacagaccta 41940 attgtggtaa tcaaatcaatactgctactg accaaaggac tgaaaactta tagctcacac 42000 actgtagatt aatgaaggaatgttacaaga ccatcttacc ccactttatt cgccttgggg 42060 tcaactgtaa caagttgtgtcatttctact ctgtgtgatg ttcctcacag actttgttta 42120 ttttcagcaa taacaattaataaggatggt taaacataaa ggcaattcat agattaatac 42180 actatatgtt ttgtatcattatgtatttca cataaaaaaa tcccaccaaa ctgtcaagaa 42240 aaatctgatc tttttaaggttaaatgttca atgtttagaa tatggcaatt ttgtaagtaa 42300 atacttttac atgttaaatatctaaaaact cgaataaact aaatatattt aggtaaactt 42360 ttttactact gtgtatttctgagttttttc tattattatt tgctgataca cttcaacaat 42420 gtttgtgatc aattgtacttcaagatgtgt gctttaaact gtttctctag aaaacaccaa 42480 atttgtaatg ttaaaaaccaaaccttttgt tttctttctt tgggcttctt tttctttggt 42540 gatattggtc catctttttcttcatttact tttttctttt cctttttaat ctgtttttgc 42600 ttctgttttt cagattcttcttcttcatct gaactgcttt ctgctttctt ggttttattc 42660 ttaggaactt tctttggtggctgcagatta attcctgcat ctgctgtcca gtcagagtaa 42720 tcactggagt agtcactagaaggagagaag ggattattag ataacacaca agataaaatt 42780 ttaagacttg ttttataaaaacgaaaagaa agattataat aaagagaaat gacagaacaa 42840 atacttaaac tacaaaaaaacttccctaat tttcaactca tcttcaaaag tttcttgaaa 42900 ttctataggc tttacttaaatatcgcaaaa aaactccccc aaaacctgaa gatacataaa 42960 gtcacaactt taagtgaaaaaacaaattta agtaccttcc aagattttaa gaaaaatact 43020 gacttctgag tgttgcatatgttacaaatt ctgtgagcat ataaaaataa gagggggtca 43080 cttttctcag ttctattgacagcaaaaaga taaccctgga gagcacagaa ggtgtcaaca 43140 ttaaggagat atggggattccttttttaag gggaggtggg agttccagac aggggaactc 43200 ttatggtcca gtactagtgctctcagggta gctggatatt gaactggcag agtcagaagt 43260 gttcctaccc aggggaaagactgtgtttgc aaactttact ctgcatgtaa agtaacaaaa 43320 tttcatttag ataaaattattctacctacc tacaccctac acgttaggtg tatcttatgc 43380 ttcaaagcat gccatgattcagaaaaatac aggccttact atattttgta tactgcttcc 43440 aatcatgttt gtcatttctttttagtttac cttcattgac aaacgattta ctgaaccaat 43500 catgttgcaa aataaagaatctagttgtat tatcttctat attaatttta gtatgtgagc 43560 atatttactt attttgtacaattttatgaa cataaatgtc ttaaaggaac ctaagttata 43620 ctatgttaaa agcaataattagctttccca gatttaatga tatatgacct catgcctcta 43680 aaaatactgc tgttaacattaacactgaaa aagcagattt ttctggagct ttattccatt 43740 gtcactaacc ctccccactacccctctcca ctgtccaaat gttctttata agcacgtacc 43800 taaatctctg attatcctaatcatcccaga taagaatcaa ataattaaga tgttctctag 43860 catgatttag tgatttcactatgaaattta aaatgatttt taagaactta cactattttc 43920 agctatgcta ttctaaaataggttgtcttc aacttatgag cattttattt atactagctc 43980 cagccatggc cactgtaaatggtacctgcc aaatcacaca gttatcactc tctggagtac 44040 ttggctctta cagaagatcttctgctgtca gcataaacat aattacaaac tccagagtcc 44100 agcattcttt acaaccgtcctcaactgcta aaaccaccac tactctttta atacaggaac 44160 tcctatgtca tctcagggtttgaaatactc tgattctgct gtcgagccaa aagaaattca 44220 atttttcctt cattgacctgttttgaatac agaaaactac tagatataac cacacacatt 44280 tgcacatcat taccagaaatcactactgtg ggaataggag agcccttgat tgtacaactg 44340 aggaactctt acagcctctacttcatactt tgtctcgtct attttaagag ccactaaggt 44400 gggggataag tgtagcagctaatcataatt gccatcccca aaggctatac tctctttttg 44460 ctattaagac cttgcaaagttagccaaggt cataagctct gcaacaatgt gaatcgccag 44520 tataaggagt tgaaggaatcctcactggtc tggtcaaata aggtaggcat aacaagaaaa 44580 aggagagctt attcctcttatcattagtat tccataaatt ccactatata agatagttaa 44640 ctcaggaggc ttgcattgctttcttaactt catacttttc aaaaccagta atgaaactgg 44700 tttgcaattc aacattataacggtattcag aagaaacaat actaagatga taaagttaaa 44760 agcatcattt tgcagatctagttgcaatca ccaaaaaatt attttctata gagaacatat 44820 atcagaaaat ctacatttcatacaacttca aaaactctct gaagaacttt gaacttacag 44880 agactttgaa acgtgttgctggttaaaaaa aaaaacacct ttctaaagac tttatataac 44940 atttggaaaa ataaaaagcattcatttacc tagaactgcc atcactgtgc catgctctct 45000 cttcttcttc ggatgttccaccactgacag caactacttc gccttcctaa gatatgttga 45060 atacatgtct tattgcataattttataaaa taacatttta tgattacaga aaatatcagt 45120 gatatcttat aatatcagtcatattgggat atttaaaatt tgatttaaat tagttgcaaa 45180 gggtgttgtg gctcacgcctgtaatcccaa cactttgaga ggtcaaggtg ggcagatcac 45240 ttaaggttag gggttcgagaccagcctggc caacgtggcg acaccctgtc tctactaaaa 45300 cacacaaaaa attagctgggaatggtggca gatgcctgta atcccagcta cttgggagac 45360 tgaggcacgg aattgcttgaacccaggagg cggaggttgc cgtgagctga gatcgcacca 45420 ctacactcca gagactgtctcaaaaataat aataataaaa taataaaaga gtcagctgct 45480 tctctttaaa aaattagttgcaaaatacag cttttacctt tttttcacaa ataaatgaga 45540 atatgtaaat gtatataaagacataatact aatattggat tcagagcaat cctacagatt 45600 accattgtaa aagcctcataacgtatctag ataaaatgat aacaaattcc atatttacat 45660 ttgaaattaa tttttacttcttgagccttt ttaaaacact aagctttctc ttctataggt 45720 gctttgagaa ggcacatttatgttttattt attataggca catttatgtt ttacttatta 45780 aaacagctgt cccatataaaaaaggatgtt ccacttctgg tcttatttta tctaaatggt 45840 aaaggattaa aaaatacttaaacactctgt ttctctttgg taaatattca tgagtaaaca 45900 aagaatatta tctgtgaaagcattttcttc ataaaattgg gttttttgat ggcaaaaatg 45960 ttgcatgtct tcctcacttaaataaacttt atgctccaat aacaataaca cctcatattt 46020 attaagcttt tactgtatgttacaaactat tctaagcact ttgtatgtat caccccattt 46080 gggcttgaca atgcactattggtgatagag agttacttaa ataaacaaac taaagcttta 46140 aaaatttgag aattttgcccaaggcggcac aactaataag caacaaaact tgatttaagc 46200 ccaggtcact ttagtccaaaccctggacaa cattctgtaa gaatggtgtt acttacttgc 46260 tgggcatatt cagataacttttaaagagga caatggggtg gattctttta atatttaaat 46320 aaaataatat acttgggacaaaagttttcc cattttgatg ttttaatgaa gaatgtgaat 46380 tatatgtcta ttccacagttatgaaaacta agcaaaaatg aaaaaatcac atttgcatat 46440 tttattaaca aaaagcatattttattaaca aatttaatca ctgctcgata taacaaatct 46500 aagcaagtga tatgatttttcccacatttt gtgtgttact tccttaaagg ggggaaaaag 46560 aaacagaatt attcctacattccaaataca aaatactaaa gtacaaaaca tctgaaccaa 46620 aaaaatcaga attctttccaattaattagt atactgtgcc caaagtgata ctttgttctc 46680 aatggactct tctagaaatatattctaaat ttctaaaagg atgttaaagc ataaataaat 46740 tagtttgaag acacttgaaggacttgttgt aacagatgtg tttctggaaa tacagttctt 46800 aagtttctaa taaacagaatattttaaata ttatatagaa acttaatatt tagaggaaac 46860 tctttcaaaa ataaagagacattttataag ataaataatt agcccacatg tattttatgt 46920 tttgtatgtc tatccaaattaccatgtgtc aaattcatat aatcagtata tttctctttt 46980 tttgccagaa tgaatatatcattttgacct ggctatatga ggacccaaag ctattggaga 47040 ctaacttaaa ttgtggttagaatactctca gtttgagagt taatgttgcc ctggataaag 47100 agaatatatt tagagaattctcatatatgc ctagcatttc aaagcacaac atggcttcaa 47160 aagtgtatag tagtcaatatctaaaatgat tacatctcta acctgtaaag aaggaaggtg 47220 atgggaaagg ttgagaagaaaagaggaatg gagatggttt aactgcttaa taagattggt 47280 ttatgattgc aaattgattgccttcactga aataatatat aatttagtaa ggacagtaat 47340 atttactgaa ataatgacgcatgaggaata tttaaaaatt acactgagaa agctgtaaac 47400 tggtacagag attaaaaactaacaaaaatt gtcaaatact tattgatttg ttgttatact 47460 tacactacac tacagcttcatggtaccact taaaaagctt ggctttcaag taaaacaaac 47520 ttgcatttaa tccctgctctacctcttaat aggtgactgt atagtctaaa tatctttgag 47580 cctcagaatc cttatctataaaatgagaat aattaattca cgagtttatt ttgtggattt 47640 gaaattatgt gtatgtgtgccatgcctaga aatagatttt tagaaaataa aagctgtatc 47700 ataagacccc aaaatgccatatttaagcta catctacaaa catatcaata aatgcgaaga 47760 atgaaactca tatttaaaaaaataagtaaa aatgacatct aatttatgaa tgtgctgata 47820 tcttacatct gaagaactactgccattttc tatctcttct gagggtctag gagtctcttc 47880 caatgcagat cttgtacgataattgtgttg atttgtctgt tgctttttgg attctccaag 47940 atccaggaaa tgctcatgagcatgattcta gaaaaaaata aattaaattt attcacagat 48000 tgtttaaaga gcaggatttttagtttaaaa gttaaaattt tttaattaaa aaaattcaag 48060 ctgggcatgg tggcgcatgcctatagtccc agctacttgg gaagattgct tgagcctagg 48120 agttcaaggc tgcagggagggatgattgca ccactgcact acagcctggg tgacaaagtg 48180 agacaattta tcctaacatacaacaacaat aaaaacattt gttcatattt aagatatcac 48240 ttaaatggat gaggttatagtaccaactca aatattttaa cattcatcaa gttaaaggct 48300 tatcatggtt atgctgatatttacttgctg attgattagt tacaaaaatg ctgttttttt 48360 tttttctaat taatgacagacataaggatt catgataaaa gactaaacca aacactgaac 48420 tcttctgtat ctacatcaaacctatagaaa tgatgtaaga aaaaggataa tgggctatga 48480 ggcatatgta ataggcagaggcaaattgga aaccaaaatg gggatcataa agctaccctg 48540 ccactatgaa gataagatgccatgtggctg gcttattttt cttctgctgg aataaatgtg 48600 agaagtcttc tgcagatgagaatacaacca ataaacacta aaaaactgat aaagtacaac 48660 acagtgatga agacaaactcaataaacatt aaaatttata cctaaaaaac acaaaaaact 48720 taataaagct atctcaaaagtgaatacaaa ggccagccat ggtagctcat gcctgtaatc 48780 ccagtacttt gggaggccaatgtgggagaa tcctgctttg gggtcaggag tttaagactg 48840 gccagggcaa tggcaataccctgtctctac aaagttaaaa aataaaattt aaagttagcc 48900 aggcatggtg gtataaacctatagtcccag ctatttggga tgataaggca agaggatcac 48960 ttgaggcagt ccaaggctgcagtcagctag gactgtccca acgcactctg gcctgggtaa 49020 cacaatgaga ctctgtctccccaccaacca aacaaaaaag agaatcacat ccatgaaata 49080 aatgcagggt cttgtcttagaaaaaaacaa agactcaatt agacatcctt gaaatcgaaa 49140 ataaccaatt aaatttgggaaaaataaatg atagccagct gaccacataa ataataactg 49200 gttattccag tttttgcgaccacagacgct aaaaatatgt gagtgtgcat gcacacacat 49260 acatatatgt atacatatacatatcattcc ttttatttct taaaaagtcc tcaaagtact 49320 actgaattaa gagataagcacatcttttaa ttttaataga tattaacata ttccatccat 49380 aaaggtagta gcaagcaatacaaactctca tcatcattat ataagtttat ctcagcaaag 49440 gatgcaaaaa aggtacgctttccacttacc atgaaaaagc caaccaatca atcaagcaaa 49500 aaacaagatt atttcagaaagaaattttcc tttattatac taacaggaat tctagcattg 49560 tgaggtccta ctgatcccagggtatgatac actcagtaaa gaaaaaagga ctacttgagt 49620 attttgaaga gatgagtaataaaacagaaa agtgaattct agagaagaag actgatttag 49680 gagttttaaa aaactcaaatgaaaaaaagg aaggaacacg aagctggtga agaaggccag 49740 ttatttattt ttcctttgtttcaataattg ctttagatag tgacttggac ctaaaaagaa 49800 gtttcacata ggcttcctcaatttcagact ctaaggctct gaagctttca agctaagatg 49860 tttttctcca aaataaaagaaaagaaaaga aaaaaaggaa aaagcgatat ttgtgattcc 49920 ttcacactca ggaagtacgtatctctctca attaggccat gaccaattga aatctactgg 49980 gtgcaacagt ttttccagagtaggatgaca gaaaagccaa taagtcaaaa ctattaggga 50040 caatctacct ctcttaatgaagaaaatgag aaatattatc tatagcagca ttagctgact 50100 tgattatcta gaataatgaatagatgcaag acaccacaaa aacacataga aaaacataac 50160 aaaatgctat ttttagactgtacaaagatg gcacacaaga ttatgaagag ctaaagaaag 50220 ttcttgatga ggcttcagtgtaatttatta gaatttcatg agtatgtaag aattggcact 50280 ttgggaaagg gtatgctacaaagcagaaat ggaattaaaa attttaaata gtaaacaata 50340 gataatccag agataaccaagatttactat gttaattttt atcattaacc tgtttataat 50400 accatgttaa attacaaaatggagccttaa aatggtcact atacttaaga agcaaatatt 50460 aaacatcaaa ataattaatatgtacctttg agacagtggg tattttattc tcttttggaa 50520 cagttaagtg ttttcttttctcttctgacc tgtaagtctt tatttcttct tctccctttg 50580 cagttctcca ttcttcttgcctactgaaag acaaaagcca tatgcattaa tctagaattt 50640 tacacataac tttcctccaaaaggaatgtt aggtatcagg aaaggaacgc tactcctgat 50700 gttttatttt aagatggaagcatgtgataa agatttctaa gtttaatttc ataggttgtg 50760 ggctcaggac atccggcattaaatgactga aataatggaa agacaaactc tgtctacccc 50820 aacttgatac tactggttcctgctatggtc tctggcaaac caagtattag attctgggaa 50880 tgtggtgatt cctagggtaatttttccaag agtgagaaat tggatttttt tttttttttt 50940 taggataggg cctatgctttgataatcttc tgttccatat agatagctgg aatctcttta 51000 aaaattcaat acaacagaccctgaggttac acggaaagcc ctgaaagaac tacactcttt 51060 ccagagacag ggaggtcaggtttcaccgac tgaaaaaact caaaccatca aggtgaaact 51120 gaacaacaca aattgaggaacactaatttt aaactttaat acaaaaaatg aactcatgag 51180 aagataattt tattttttatttcaatatct tacaacttta aagtttttga aatgcaaggg 51240 tatttgaaat ttaattctcccttaagattt tataataaga aggtagttaa tactaaaaca 51300 cagtgcaact atatactgttgatatttctt tactagatga tattaatgtt atcatgttac 51360 ttaacggcac aatctccattgtggctggcc ataattctga atggaaaata aaatgagcaa 51420 atttaaatct tgtgaaaagaacaggcttgg atttaatttt tttgttctta attttttttt 51480 tttaaattaa actttttactgcaataatta tagattaaca tacagttgta agaaataaca 51540 gcgattattt gtatcctttatccagttccc ccaaatagta actttttttt tttttttttg 51600 agatggagtc tcgctgtcgcccaggctgga gtgcagtggc atgatctcgg ctcactgcag 51660 gctctgcccc ccggggttcacaccattctc ctgcctcagc ctcccgagta gctgggacta 51720 catgcgtccg ccacctcgcccggctaattt tttgtatttt tagtagagac gggggtccac 51780 tgtgctagcc aggatggtctcgatctcctg acctcgtgat cccccccacc tcggcctccc 51840 aaagtgctgg gattacaggtgtgagccacc gcgccggccc aaaatggtaa cattttgcaa 51900 aactttgtat cctttatctaattcccccaa atggtaacat tttgtaaaac atggtacaac 51960 atcagaagga ggatgctgacatttatacaa tccactgatc ttactgagac ttccccagtt 52020 ttacttctat tagtttctattagtttgtgt gtgtgtgtac acaggcatac attgttttac 52080 tgtgctttgc agatagtgcatttttttttt tcacaagctg caagtttgtg gaaccctgca 52140 atgagcaaat gccatttttcaaccacatat gctaacttcg tgtctctgtg tcacattttg 52200 gtaattctta aaatatttctggctttttca ctaccattat atctattatg gagatctgtt 52260 gtcagtaatt ttttatgcttctattgtagt tgttttgaag caccatgaac ctcacctata 52320 tagaacaatg aacttaactgacaaatgtta cgtgtgttct gactgctcca ctaactagcc 52380 attgccccat cttctccctctcctcaggcc tcactattcc ctgagacaga acaatattaa 52440 agttaggcca attaaaaaccctaactgatc cagtgaaaac atctctcact ttaaatcaaa 52500 ggtagcaacg attaaactctgtgataaagg catgtcaaaa tctgagacag gctgaaagct 52560 atgcctcttg tgcccaacaaccacgttttc aatgaaaagg aaaagctctt gaaggaagtt 52620 aaatatgcta ctccagtgaacacaggaatg atatgaaagt gaagcaggct tgttgccgat 52680 acagaaatag tttttgcggtctggatagaa gattaaacca gctacaacat tcccttaagc 52740 caaagcctaa tccagagcaaggctctaact ctattctctt ctatgaaggt tggaagaggg 52800 gaaaaagctg cagaagaaaagttggaagct agcagaggtt ggttcatgag gcctaagaac 52860 tacctgtgta acataaaagtgtagggtgaa gcagcaagtg ctgatgaagt agctgcagca 52920 atttatccag aataactagctaagatcact gaagacagta gctacattaa acaacagact 52980 ttcaatgtag taacagatcaaacagccatc taaatggaag aagatatcat ctggactttc 53040 acagctagag agaagtaagggcttggcttc caagcttcaa agggcagtct aaatcttttc 53100 ttaggggcta atacagctagtgacttcaag ttgaagctaa tgctcattta tcattccaaa 53160 aatcctaggg cacttaagaattatgataaa tatactcatc ttgtgctcca taaatgaaac 53220 aacaaagtct agatggcagcacatctattt atagcatggt ttactgaata tttttagccc 53280 actgttgaga cctactactcggaaaacatg attgctttca aaatattact gttcattgac 53340 aatgccccta atcacccaagagctctgatg cagatataca aggtgattag tgttctcttc 53400 atgcctgcta acagaacatccattctgcag cctatgggtc aaggaataat ttctattttc 53460 aagtcttttt atttaagaaattgcatttca taaggctata gctgcactag ttattctgct 53520 aacagatctg ggcaaaatacattgaaaacc ttctagaaag gattcaccat tgtagatgcc 53580 attaagaaca tttatgattcatgggaagag gaaaagtatc actgttaaca ggagtttgaa 53640 agaagctgat tccaaccctcatagatgatt ccgaaggctg aagacatcag tggaagaagt 53700 tactgtagat gtaatggaaacggcaagaga actataatta gaagcggcaa ctaaagatgt 53760 gactgaattg ctgaagttgcataataaaac tttaaatgaa tgaggagtgg ctcatgaatg 53820 aacaaagagg tttcttgagggaggctactc tagtgaatat gctttgaaca ttgctgaaat 53880 gttaacaaag attgtagaaaactatatgaa cttggccagg cgcggtggct catgcctgta 53940 atctcagcac tttgggaggctgaagtgggc agatcacaag gtcaggagat caagaccatc 54000 ctggctaaca cagtgaaaccccatctctac taaaactaca aaaaattatc caggcatggt 54060 ggcatgcgcc tgtagtcccagctactggga aggctgaggc aggggaattg cttgaaactg 54120 ggaggtggat gttgcggtgagccgagatca cgccactgca ctccagcctg ggcaacaaag 54180 taagactctg tctcaaaaagaaaagaaaag aaaattacat gaacctaata aagcaatggc 54240 agggtttgag aggactgaccccagttttga aataagttcc acacagaaat atttcatgag 54300 aggagtcaaa tcaatgtggcaagctttatt attgtcttat tttaagaaat tgccacagcc 54360 actacaagct tcagcaacctccactctgat cagccagcag ccatcaacat cgaggcaaga 54420 cccttcacca gcaagaagagtataatcact gaaggttcag atggttgtta gcgtttttca 54480 gcagtaaaga attttcaaattaggtatgta gtttttttca gacataatca tattgttcaa 54540 ttaacagatt atagaatagtataaccttaa cttttatacg cacttggaaa caaacaaaca 54600 aaatcatgtg agctgctttactgcactggt ctgaaaccaa acctgcaata tccccaaagt 54660 atgcctgtat cttagcaacctaaatctgtt ctccattcct atacccttgt catttcaaga 54720 atatttcata aatggaatcatacaggatgt actttgaaat tatttttctc cactcagcat 54780 aattccctca agattcatacccattgtatc aatatgctgt tcctttttat tgcacagtag 54840 tagtccatgg tgtgaatataccattgttta accatctacc cactaaaata catctgggta 54900 tctttctggc ttttgggtattacaaataaa gctgctatac atttatgttc aggtttttgt 54960 gtgaacatga gttttcatttctttaggata aattcccaat agtgcaactg ctgggtcata 55020 tgacaggcag ttccatgtttaggattttag gaaagtgcaa aactgtttcc caaaatggct 55080 ctatcatttt acattcccactagcaatgca tgagtaattc agttttctct acatcctctc 55140 tagcatttgg tgctgtcacttattttttat tttaaccatt ctgagaagaa tgcagtgata 55200 tttcactgtg gtttcaacttgtatttccct agtggttaat gacattgatt atcttttcat 55260 gtgcttattt gtcatctatagatcctcttt ggtaaatgtc tgttcatgtc ttttgcccat 55320 tctccggttg gattctgttgtttactattg agttatgaga attatttcta tgttacttag 55380 ccccctgttg ggtatgtcattggattccat tttaattaat ggatgaggct gacccatttc 55440 agagagcctt tttaaaaggaaactttagac tacccactgg agagattctt aggaagattc 55500 ccataggatg agtacaaagttttagagaca aagctccagg aagcccaaag aaagaatatc 55560 tgttaaagtt atggccacagtcttgcttga ccataggcca atgaatagtt aagcccaatg 55620 ataaaggaat aaaaggatgaagaatatttg aagagaaata aatcttcctc actcctcagg 55680 ttcccttcca tgtgcaggagcctcaaccta caactagcaa ccttatctcc tgactcattc 55740 ctctccagag gaggagtaaattagtcaact gatatgctct ggaagaaaaa cccagcttag 55800 cacagcccag ccttatgccattgtgtgcaa ttatacattt ggccctgcat cttaaagaag 55860 caaaccacat gtcctgtcccacaaggggag aaaaactgtg gcccactgct atctgtgtct 55920 ggtgaatatt actttttgttactgatatgg tttttgtgga atattacttt ttgttactga 55980 tatgggtttt atttcacgaaataaaaagtg atagtaacaa acagtgatag gctgatttac 56040 tatgtcttat tctccatgttatttttcaat tatttcagaa ttggtgttga aaaaatgggc 56100 attatttatt tgacccctttcaaaccttaa cattagaatt aaaaagtaaa caagaatcta 56160 actaaaaata tgccatgtgagttaattaat ttatgacgga taactgggca tatttgtcat 56220 aagaaagtgt aaatgtatacctttggtgtg tatttaattc taaatcctaa cataaattca 56280 aagtatgtcc aatcaaaaagcataatctat atgaacatta agaccaaaat tttaattatg 56340 taattactat cttctgagttgaagaactag acaatcttaa attcaaattc acattttgac 56400 cttcatactt agaacacacttcatacacag aaatcagcct tacttaagtt catataggcc 56460 tcattcatga gtatttcatgactgaagatc aaaaggaact ggatataaac ttccctcatg 56520 gcatggtcta agagaatagaattttattaa atcaatactt ttaaagtcat aaatgtatac 56580 ttttaaatat aaatattttaatatatataa aatctttttg tattttccaa tttatttttt 56640 ttttgcatct gaatatcatgtgaatggctg gctaaatcca ttaaaaaatt aaataattac 56700 aacaaacttt ataaaatgtattttaagata tagttaaaca ggacaaacca agactgaaat 56760 atgctactca ataaaacctcctatttggtc aatccaaatt tatgattttc ctgttgacct 56820 taacacgtat cattcttatcatttacataa atcattctag aaataaatat attttagaaa 56880 cttaattttt ctacagtcatgaatagttta tactgccctt ccagaaaaat ttcagaggaa 56940 ttacagagct gaaaataacagctgtgaatg ctgttaactc caaaatgaac ccaaggaact 57000 atggtacata aaaattcacaacttccctta cctggctaca ccagctgata gctcgggtac 57060 taccaccctt cgactccaagctaccagatc ccgctctgtg gctatttcac ttcttggtgc 57120 gttgctgtgc atttgccgtacaccttcaat ttgtccacta cgtcttagtc ctacgtttgg 57180 tggtgaatga acctctgaggtagaacttat ggagcctaag tgaaaaagtt actatattaa 57240 gttctactta gagatatttctccattagtt tataacagaa aaaagagata aaacactatc 57300 ttccataaga aacttcatattgtggcaaaa taattaaatt accatatcag gaactaaacc 57360 acaggcaaaa gtggtttaatgaaaacaaaa catggttatt cagttgatta gataagtcaa 57420 tgaatcataa ctatagactattaagcccca aggatacaaa atcattactt taaaaaaatg 57480 ctaagtattt ttgagaaaacttcataagaa gcaaactaga caaacccaag agtattaatg 57540 gttcataaat ttgttttgactcttaaagtt taataatata caacaataag ggtgatgaga 57600 tgttcaagaa tgtggctttgactattctac atgtttacta tagaaaatgt ggaagacata 57660 cacatttaaa aactcattatctctaacttg aaatctcatt atgaaccatt ttcttaggtc 57720 attaaatatt cttcaaaaccatgatcattt tggcaaccta atatttcatt ttacggatgt 57780 accataattt ttttaaaccacttaacactg tgggagattt aggctgtttc aaatttttaa 57840 atatttcact taaaatagaatacctgctta cctctactta aacggctggt attactgata 57900 actgcttcac cagaacgtctcaggtcttgc tcctgttgta gtctttgaat catgctgtcc 57960 agtgggctga tctcctggtttgcttgctga cttaaaactt gattcagtcc tatacaatac 58020 cacacaaaat attacgaatattttagctac tattcaaacc attttactca ccaacctcac 58080 ttatgagttc agaattaaacataaatgttg cttgggtaaa agacttaaat gatcaactat 58140 aaatgatggg agttaaaaaaaaaaaggaaa gaaaacatct gtccatctta gtttatcaaa 58200 aataacgatg aggatggttgctaactttta ctaagtgttt atcatgactc agatactcat 58260 aatccgtatg gtaactccattaggtatgta taaacaactc cactttatag atgagaaaac 58320 caaaataact gttcgaagtcacatatctaa taagtggcaa tagtaaggtt ttccacttag 58380 atcatggttt cttttaaaatgacacatctg attacccatt ttcttaaaaa aaatgtttac 58440 tgcctcattt attcaatacattattgactg tctactatat gttaggaact acgccaggta 58500 ctgagatcta gtggtaaataagggacatga agatccctac tctttaggga gctgacatac 58560 tgatggggaa agtaaacaataacccaggag ttaatacaga gtatgaaaga gaggtgttga 58620 aataaagaag gtgatggtgggtcagaaaaa tcagagaagt cctctcggac aaggtagcat 58680 ttgcgctgag atttaaattagatagccaca taaagatcta gataaggaac acttcaggta 58740 gaacgcaaga ggtacaaacgctgtgaagca gggagaaact tgtattttaa tccatccaag 58800 ttttccagca ttaattcttacttgtcatag aggaccactt gacttctgcc cttctaaaaa 58860 gtaaacacct tcatgcactgaaacttttga acacaatatt cccactataa agataaacat 58920 gacaatctct taacttaccattccagcacc aactaaaatg gcaattccat gacatttcct 58980 ctgtgaaatc tttccaattacttctgaaag aattacctgc taccctcttt cacttcctta 59040 aacaacccat acatatctaagtattcagac caatataaaa cataaatgaa gtccaaaccc 59100 attagttcct caaaagcatgaactgtctca cttaccttat ctaaatctag tacaatgcta 59160 ggcattaaaa aatattcactcttgctgaat aaatttttaa aaggtatatt ataaaatata 59220 tgaaaaatat tgccatgagtataaagaagg gagcaattag tatcagccat acaagtatat 59280 gagaagatct gatcagctcagaattttagg gtgggcttaa atggtaagaa aagagagcaa 59340 gaatattctg aaatgaagtagtagtaagaa aggtaaaagg aaaaagaaat tacatgtatt 59400 acatgcataa tttcatttataaaagaaaac taaaattcaa taggataaaa taacttgttt 59460 aaggtcacca aagtagaagtagtaaaagca gacagaagta aaagttcaaa tgtcttatac 59520 ttctttcctg gtttgctgttggaaaaccat gttgcaatac tgatgaataa tctgatatag 59580 ctcaagttta caactgaaaaaaacacattt aaagtatgtt gtatggtgcc aatacaacaa 59640 gctaatttat tattataataactcaaatct atttttccct aactctgaga gatttcccag 59700 aataaatttt attatctggatttgcaaata aaaagctaag gttttttttg aaaagaattt 59760 tgcttttgtt ctgtttttgtattaaccaat tttagactca ataagtctaa aatatgacaa 59820 aaaaagattt ttactctgaattctgagaat cagaacactg aaaaattttg ggactcatta 59880 caaagccagt attattgctatggattctct tatggatacc aacaactggt atctatttca 59940 tttttaagat tatgcctattttatatggaa gaaagaataa tggactgaga atcagagctg 60000 aggttagagt ccctgtgattctatgacaca ttaccattaa attttgaatt ctctcaacct 60060 gcaggactgg aatatcaaagatacaggatt aaatattgtt tatgaaagcc ctttataaat 60120 tggtaaatgg atttaaaaagtaataataat aattaattag cactgatact ttaataaatg 60180 agtcttttcc ttatttccctgtgtctgaaa ccctaaagta gctatctatt ttgaggcttg 60240 ggaacaatct gattttgccaattcctctcc gagagactga agacatttct cttaatttca 60300 gtcctatgac cagaacttctctaatactga aacttatcta atctgagtct gagtatctgt 60360 ccatacttct cgaatactacttattctttg agttcatgct gtgtccacgt actgagacac 60420 attaatctca caaactccagataagtccac tggactgcac tactctagga gtagcagcag 60480 gaatgattcc tctaatgcttcttctcaccc tccattctaa gtggacgtgt ctaattccaa 60540 gaggagcccc ttctatccagtatgtccatc tttattgcaa cttcatgcta aatcctttaa 60600 gaaaaataag atgcacgtttgaggttgatt ttttctgtgc tccttacaga atctaatttc 60660 attatttaaa agtcactcaacacaaaagct acttagaagc ttttgtcgat tgaagtctag 60720 aacttaaaat attttcataaatatttttct agtctaaaaa tatagtagaa gtattcataa 60780 tgacaaaact ggtttaaccttctttacaga acctttcctt atttttactt aatacactag 60840 tgctgcattt cttgtcaaaagagggaaagc agtttgtaga ctttgactcc attttaactc 60900 tcatttaatt cttcaacactccattatact tcactaaaac agctctcaac actttccatg 60960 tcaatcctct tataaacctttaaaagttgg taacttttta aaacatcttc aatgtgaaca 61020 ggcaatctac aatctctctcacatcatgct attattccct ttagtaacat tcatcacaat 61080 ttgaactatg tatttgtttattctaatgaa ctgtgtttat taatctacta acccattcca 61140 tgaaagcaag gatcatgtttgtttaatcca ctactgaata gccatggctt agcaggtgtc 61200 agagacagaa gagattatcaataaatgttg ctgagtaagt aaattaattc acttgtttca 61260 caccaaatac aggaactaccttattgatcc ctaggggtta caaatggata ataaatcaaa 61320 attattactg taaatcgcccatgttccata attaacttgt aatccttaag catgatcaaa 61380 gacctgtata aaagtataaaacatactttt acttcttatc cacttaacaa ctgcaaacaa 61440 agttttactc aattagcaattttaacagtt cggtgggaag aagaaaattt gattgtctaa 61500 gaaaatgagc acctacctgaggaagttact cccatctgag ggatgagttg ctcctccctg 61560 caattttcac ggccaggaactaatctttga tatcttgatg gatgagggtt accatcaaca 61620 tcaaccaaaa aagggggaggcataagatga ggtgcttgct gagtctgttc atctaataca 61680 aaattgttgg catcacgaataagtggccga taatcactat gaaagaacat ctgatctgct 61740 atctgcaaaa agaaaagtccataaaagact ggaaaaataa aaatgtatca ttgtagaaaa 61800 aaagtctaca tcatttctaatagaaagcaa acacctgaat acgaataatg gtattaagca 61860 acaattttta aaatattattttcctgaatt aattgtaaat aggtatttta attttctacc 61920 ttaagtatta tgatcagaaaagtagctgct ttaaattttc tctgaaacaa gtaagggatt 61980 atacacagga gtcccctcttatttgcaatt ttgctttcca tggtttcagt tacctgtggt 62040 caacctgact ccaaaaatgctgttccagaa ataaacaact cataagttta actgtgcact 62100 gttccaaaat gcataatgaaatcacgtgcc atctcacttg ggacacaaat catccctttg 62160 tccagcatat ccacattgtctagatatgct acccacccat tactgtatag gaaaaacaca 62220 gtgtgaatag ggtttggtactttccaaggt tttagacatc catttggagt catggaacat 62280 attccctgtg gataagaggaggctactgtg tagaaaagct accactaaaa ataagctatt 62340 caatattcaa ttttaaattaaatggtaaca tcaaatctag tcataaatca ttcaacagta 62400 tttttacttc cacagagctaccatgcttta tcttaaatcc ttaggtatac agtaagtatg 62460 atttgtgtaa tattactataaaaatcacat aagattttct aagggttaat aagcattttc 62520 tctaaatgtt ttgagatgatataaaattat taatataaac tcaaccagga cataaatttt 62580 attatataaa atttcactggttaatttgca attttttaaa ctaaattata aactactcaa 62640 tatttactat cataaccttttataccattc caccacaagt aagcaattta attcttttag 62700 tcactaatct taaagttggggtctttaact gctgagcaaa gtggcagggc atatgcctgt 62760 agtgccacct gcagttatttagcaggctga aatgagagga ttgtttgagc ccacgaattc 62820 aaagccagtc taggcaacatagtgagacat ttcaccccta ctctgtaaaa aaaagccccc 62880 caaaaactgg acaggatctttaataaaaaa cattaactac aatcaggtaa tataatacat 62940 ttttaagagc cacatgaaagccacagattt gtaccctaga taagtacgta ttatctatat 63000 taaaaaaaca ttttacataatttcagagtc ccactatgga taacatcttc catctccagt 63060 ttatataccc caagttaagaattccaatct agattgcccc aggaggctaa gagttatttt 63120 tttcctgaaa tatgcagattttcaaataat aagccctatt aaagtgagat ttaactgctg 63180 tcttcacctt cctttccgaaactaagtctc cagactactt aacacaagat tcttcgaatt 63240 ttatcctgaa tgtaaagatgctgattctca cccactccaa aaacatacaa cccctaaaca 63300 tgcattaaaa aaaaataaggacatgatata tagtcatcat actctacctt gtcatatttg 63360 ctactggacc caaagccaaaaattaaaaga tgtccatgag agtctgtgca tgcaaaatgc 63420 tgaccatcag gagagcatttgcagtcaaat actgcgccat gtccttggcc ttcaatctga 63480 aatatattta accaacagtaagaaaactac cattaaaatg aaaagaattg gtcactatta 63540 ttacaataat tttaagataaaagcatacat cctaatgaag tgaagattaa gtaaaacaag 63600 cattgtacag taataaaatttatgaatatt catgaaaagt gccagattaa tagccttgaa 63660 aaataaagta ttctatccacagaccaaaca caattcagga aataaaagaa taccaactcc 63720 cccacccata gaattctgcttcatgtttta aactcagatt taacacataa ttatgtctta 63780 cactccatct atctccgttcaatcatgccc tttctgcaaa agctgacatg tagcaactgt 63840 acggattttt tggtaattcttggaagtagt agccagagat cattgctcaa atgacactag 63900 attttattat ttttggtaataaattccctg gtagtctgac tcgtctttta aatggtgaat 63960 ttcaaaggtt aaagaaaaggttttttttac ctgataattg ttttctgttt tccagttcca 64020 ttaatccaga acgaatgggtttcctccctg caacctgtca atcaaacaga ggtggccaat 64080 caccactctg aattttttgctctcagtgct tcttcagact atgttccagt tgaaaacttc 64140 tttagcagtg ttctgaaagaggtaaaaatt ctaccctatc taaagcacat ctagggactg 64200 aatttcagaa acaactaaaatagggagttg actccctaac aaataacaac taaggatgat 64260 tttcaacaaa tgctgttggatttctggatt agcagaatcg gaacacacac acattatcag 64320 gtaagaaata cctcctttctgttccggtat ccactgatct agaacaaatt gagctttatt 64380 agtaatatcc caggaaatgcttggaaaaga gaaaggtagt aactttcttt ctttagtatt 64440 aaaaatgtgg cataaggatggatgtacagt tcaccaaatg cagaagttaa aattcagaag 64500 aagaataact gatttctcaaggaaggtttg cattttggta aaaagagaaa atatttctat 64560 aaaagaaagg actttacctaagaagttaat acaataccac aaatgggact gcctcaaaaa 64620 gaaagctagc tttttcctttggcttgctaa aaagaagaaa tgtgtgcaac agtgcttatt 64680 aatgctcttt tggatggttacaataataga aaagaaagaa taacttttta aaaaatgtaa 64740 ccatattaga taaaactaggaaaattatct aatgtttaat atacacaaaa acttagaaaa 64800 gaaaggaaat gaatcataagtgaaacagga ttatatctcg agtgtgaaga aagttggagg 64860 atgataagat aggagaagaaggtaactgat tccaagtcta ctttaaaaca attcaaaaac 64920 aagaaagaat ataactatttctccagatta ccataagggc accaggagcc atacagctag 64980 gcatttgcca aaaatgaaagactataagta caaattcagg attcaagtct ttatttttca 65040 gtgttttcct aggcaaataaaaaaaaaagt tacatgaact gttataaata agcaaccaca 65100 tgaacaaagt acacctctaaatagactttt atatcaaaaa ctaaaaatta ggggattgaa 65160 actgccttag ccatgtgttgttaaatgatt tttttttaac tcagttcact caaaatttca 65220 cagaagccaa gagagagaacaaaaaagcaa ctactttata aatctactct aataaatgtt 65280 tccagaagta taattacaagtctaagatta caatttgaag tagagtggag acttgaaagt 65340 agtccaattt agcaatttcaaaggaaatct gataaatgtt cctaagcatg gtatccttca 65400 tgtgttgttt aaacaaacattttttctttt tgggggtgag ggttgcgggg caagtaggac 65460 tgatcaaccc ttgaccctattatttatcaa tgttgccaca tttacagtta gtagatctct 65520 gaaataatct tggggacagttgaagcttat aaagctctaa aagagcaaag aaaaaatagc 65580 aatcatattt aagatgcctgtgtgtcctat ataacacatt tcattgtgaa tatggcaaga 65640 cagtattaat tttcttggtataaggcatct gtttaactcc aaagtgactt ttatatggag 65700 aaaatgaaag tatatttcaatcatatcaga aaaaagaaaa ggatattatt tggattaacc 65760 atttgtttac taaaggaggcattaaaagaa tctgctttac tcatgaacca gttagaaaag 65820 gtgcctctaa cttcatcaattaaaagacca actctctatt tattaataga tcctcagaca 65880 ataaacaccc atatctataaactgcagact aggttttcca gaccaggctt ccaaacagtt 65940 gatgatataa aacaggaaaatattttactt tctctatatt aactaaaaat agcctaactg 66000 gttttaaaat gtatggtacgattaagtaag ccaatcaaaa gaaaagaatt ttatcttttt 66060 aaacaagggt caaagtatttatgagtaaga attctcaaag acaaaatttt aaatgaaggc 66120 actatttgaa tattcacatctactagaaag cagtaaggtt tatcttcaaa aacgaaaaga 66180 aaataccctc tctcaccaaatgaaaggtat ataagcctat cataaaatta aatgcactgc 66240 gtatcaagaa aatgtgtcaacataaaattt aatactacat atagcttatg ctagctagca 66300 cttactgcag ttgtagtaaaataattagaa atagagtgaa actaataagt aatgagaaat 66360 tatcaaaata agtgcattttagatgaacta ttcctctaat aaaatcaagt atgcttgtta 66420 tgcattcttt tggatatatagaaataaaga ccacataaag ctcatagaca ttaaatatca 66480 ataaggttta gctgagataatctatgagac agtatttacc agtaactgtg aaaacttcaa 66540 aaagaataag aggagtaaaaagaaaataaa agtatattca gcaattattg tattttgttt 66600 tatttttaaa aggaggagatgggaggatca gatgtgttaa aataatgact cccttatttg 66660 aaaattctca tactgactaaagaattctat aaatactacc aataaatgag tagtataaac 66720 ttgttaggca tttagagatttatactaaac tttaaagaaa ttaaatgata caaaaactta 66780 tgagctaaga gctctgatgaggactcatta aggaaagaat actaatacct tttttgaggg 66840 aaggtactat acacaactaacataattttc ctgaagcaga aagatgaatg attagacaga 66900 ggaatgaggt cgaagacccaagacatctct ccatcagtaa taggtaaatc acctaatctc 66960 tgtggaatga tggagataaatgatcactag aatccagttc taaaatccta ccatctgagg 67020 ttctgaaagg tatgttgaaaaaaactggac aaatctggag atgaagtata ttaaaagcag 67080 aatgcatact aaaattcaggatctcaatta tatcaatcat gaagaatata cagagagtga 67140 atatgagaag tatatgcttctagaaaacct taacacaaag taggaaggtt aaaaaatatg 67200 ggctatctta ggcagaaccatcctcttcta gagttatttc aattctatta gcagggtcag 67260 tatgtcttgt tctttttttttttttttttt ttttaagcac accgttcatt agaagaaagc 67320 atcttaccta ggaaatactccaaaatttta aattatgtat gcaactttta aaatacccta 67380 aaataatctt atgaaatggactcatatacc aagaatgaaa agaggtgata aatggaattt 67440 atgctaagaa taacccttaagaagtccttc cttatgtatt aaaaaaactt ttagattaga 67500 gcttgccaac ctagggaaaaatatgtaaac tagatacaaa aaagactcag atgtatattt 67560 gaaataagtg ttggatcctggtcaacatgg tgaagccctg tctctactaa aaacacaaaa 67620 attagctggg tgtggtggcgctcgcatgta gtcccagcta cttgggaggc tgaggcaggc 67680 aggaaatcac ctgaacccgggaggcggagg ttgcagtgag atgagattgt gccaggaggc 67740 ggaggttgca gtgagctgagattgtgccac tgcactccag cctggtgaca gagcaagact 67800 ccgtctaaaa aaaaaaaaaaatccaaattc caacagttca ggtgttatca aattacttta 67860 aaatagttat tgcatggctgttttaatctt gaaaattctt taacttatgc caacataaaa 67920 aaggaaactg ctggacctgacttgataaaa atcagtagat cagattatta cataaaatga 67980 aaaaaaaatt attatataaaagtgattctg aaaaatcagc tctagatttt catcaaaaga 68040 aaaatattac caaaataaatatcttcaaat ttaacatcat tttgtaccca tattatgatt 68100 tctctgggga gagcaatactattgattagg ccttccttga ggcttatttt cttttggtct 68160 ttttggcata ttagcatggtgtgtcttcct tgacacaccc tcttaaggat tgtgacccct 68220 tttccattct gctaaatatatgagtatttc ccaaagttta cttctaagcc ttctgcactt 68280 ccttctcctg tctccacgagaaagtaaact atatactata agaaacactt caacactttc 68340 ttctttttac tcctagcccctctaagtagt ctatctccaa gtgccagctg gccatttcca 68400 cataggtagt tcaacgcaataaacattatt acaaatgaac tgaataaaga agtcagttct 68460 cccttatgtc tttcatatttccactaataa aaccattgtt ctcaaggtca cccgggctta 68520 acactctata aacccatttattaaatcttt cctccctgtc atcctatagc ccaaatccta 68580 atatagtcac aaaacaccaagtcatttatg tatttttttc tttacaaatt tcctaccaac 68640 tacccctata atatttcatgactaattaaa gtagttgtcc tcacacttat tcaatttcat 68700 acctgaaatt gtactactggcaaccaaact atttttctct tagcttctcg accatcctat 68760 aaaataattt actaaagcccccacaaggtt cataggtatt tatgcctatg agatcatttg 68820 aagtcactga cagttcatctcaatttgttt ttcgtcatta tttccaaaat ctactgcaat 68880 caagcttcct aaatatctaaatttctatga acatgtcttg acacttagct ttttataatg 68940 ttcctcttgt ttataaaattcattctcttt cttactgact cgattcctat ttatctttca 69000 aggcatagtt tcaattccttctcctcaaca aaacgtctcc aatcgtccac cctgacaatg 69060 atctctacat cttaagatacagcaactgtc ttttctcatt tgtcatgcta ctgtttgaaa 69120 ttatttatca atatttatcccttaaggtat attttgtata ttttgtctcc ccaacttaac 69180 tgtaggctga ctaaaaagaccacgtcttat tctcccttgt ggtcctcata ttttgtgctt 69240 aacacaaaag aaaacactcaaatatttgtt aaaatgtttt catctgcatg tttaaattct 69300 gtataatttc atataccttctcatataact atcaaatctc aaataccctt gtgatagcaa 69360 gtcatggact atgtcaaagaattactacat aaaagtaatt taccacatat aatgcagtgt 69420 gagaagctgg agagacaaactcacattcat ggcaacagat taacatgcct tttgtaccaa 69480 gatatatata tataagagagatataatcta aagaatctta aaacctgaaa gtgataatta 69540 ctaaagtgta tggtaagaagaccgaaagta cttccttacc caaagaagct gaaacataga 69600 ctggaagcat cagagagtccttttaacaca gagagtataa atataggaca ttatcttgtt 69660 agatgatgat aggaagaaagaaggaaggaa agaagggagg aagggaggga gggagaaagg 69720 gagggttggg tgagggagaaaagaaaagaa agagaaagag agagactctt ctcctgatta 69780 ataagagata acacaatatgagctgtacct attttgagct tctctttctc cctttcctag 69840 atacatacag ctacaattatctaaaactaa agtacaggtc acactgagaa catgttaaca 69900 tcagaagaag tatgcatgtacaaaaattct gggtggtaga ttggcagcct ctgctcgttt 69960 ggaacgttgc aaggagaaatatattgttct ggattagtgg acactggaac tttttttttt 70020 taaaaaaatc tcttaagtaaaagaaaggtt aagagaacaa ttataaaaat aaggaaaact 70080 ttaatcaaat aaaaacttatttggaattta cccatgaaac aacaaagtaa agcaaaaatc 70140 aaattcagta aaactgctttctattaagag acatactata ctctttgatt aaaatgaaaa 70200 ccagacagga ggcaacaaactacagctttg agtaatgaca gaaatagaaa gatatggaaa 70260 gagagataga gacacagctagggctataga gaaaagaaag agtaagagaa ataaagcaaa 70320 accgccagaa acatgaggaaagctactaaa aacatggggt ctacaaattc aactccaagc 70380 atctcttatt tactatttaatattcaaatg gcctagtact aagaaatgtg aaaagtctct 70440 atcttttcaa attaatttaatattcattta gttaaactcg tagttaaaac ttagctgtcc 70500 ggtgctaatt taatggggaataaaagacca taaaacaatt tatatttagg aacatttaag 70560 gttataatta acttctaaacctggcgacct ctttcacaga aggccctcag cttcagtcct 70620 gagagttgca cacattttcaagctatttct gggaattatt tatctgcctt ttagcattta 70680 atgggagtat agagcctttagagtttagaa caactctcat caaaacaaag ctattctgat 70740 gtttacctcc tgccaatgccaaacaaatgt gggcttacta agttataccc aactattata 70800 gtttggaata ttcttaatatacactacttg cttcagtaaa atatccaaat atatactaca 70860 tttcctctga atactcaagttatgtaagga ctgttcagtt gattcgtaaa gaaataaaag 70920 tactgaaggc ctagaatgtagtttgtttgt ttttaaagaa taaagttgtc tcataatatt 70980 ttctacaaaa ttctctttggtttcttctcc tgttcactta aaaaagaaaa acaacaacaa 71040 caaaaagaac cacaaaggctttcccaataa gtgcttttaa aagtttttag ttaaagatga 71100 gacaacagaa agggtagggggagtacaagc tacatatact gtctattcca tttcatgccc 71160 tatgttagcc tcttttaaaacatcatctca cgtgtcatat acttcttata agtaacaaaa 71220 acaaacccag cacccactccccaactgctt ttatcattga gatcctctat taggaggaaa 71280 gttagcagta aaaacaagaaaaataaaccc ctcagtttct ctggagaata ctacttgaaa 71340 gttgagaatc catttataagatttcagaat gaagtaaatt atttaaacat aaaagaacta 71400 aatagcttta tctcaattcccaatctcaaa ctctttaatt tgctgacaaa tttagatggt 71460 cccaaaataa agcacaagaaatttttaaaa gtataagtca tggcttgata cagaaaaaaa 71520 ttagaatact tattacaatgatgactatca gtgcaatatt aaaatattaa tgttttataa 71580 tcttatattt aaaaattattaaaatgtaat tactatgtat caaacaggca tttgaaagtt 71640 caccttttca cttgaaaggctttttaacat aacaggattt ttggctattt ctaaaatttc 71700 aaaaaaagaa tttacatttccataattaca caaaaaatgc agtaaaatgc tgatgaatac 71760 aaaatactaa attatatgttacatgatttc cattatcttt tgcaaaggta taaatttcca 71820 atggaaaatt caattattattcaaaaagca ggagaaatat taaagtattc ttaaaatata 71880 cttgataaaa accagtatttaagaaatttg tactaaaact gttattctaa aggtatagtc 71940 tacattcctt attttctagctgtaggtgga atggtgagtt tacttatctg ttttataaac 72000 ttcagtttta acagtcacatgaaatattat ttaatcttaa aaatacttca cataactttc 72060 accatttcta gtcaaaaaaggagtattcca ccagaattct tcatcctcta atagaccaaa 72120 gcactatata tgactagacccttcacatgg tgctcaaaaa atatttacta aactgaactt 72180 gtgattacta ctacaacttaacattaggga ttaaatttgt atgcaatcaa gtatcgtggt 72240 attttagtaa ctgaaaaacttattgattag ctacagagag ccaaatagct ataattatag 72300 ccaaaactca acattcatgatagcaagcag tgagaacgca ggccctccct cgaattgttt 72360 ctctttattt tcttaatagcaatgctggat gctttatctt ccatttgccc ataaataaaa 72420 caagcaatga aaagaacaaaagagtgaaga gcaaaaagaa ttagggcaat tagataactc 72480 ataaaagaca gacaggaaaaaaaatcaagt taaagagtaa gatgtcaaaa gatccactca 72540 gatttattac cattatgaaaacatttcttc atagacatat cactaactga gtattgttaa 72600 aagttagcta tgcagtaacattgacaaaag ctcaaaaagc caaccatgac aagatttgag 72660 tacaaccaga gtcatgggtttatgctccaa gtgcccgcat aatagctgtg tgaactcagt 72720 aaattggggc aaagcactttatctctgtaa tgtacagttt ctccattcct aagaccaaga 72780 ataataaaat ctatcttgatcatcttacaa ggttttcatg agacccaaag gaggtaaaat 72840 atgtgggagc attttggaaaccattaaaca tcatacaaaa aattaaaggt agtatcttta 72900 ttttaatgag atgaagggtggctcactttc tgttttttag cttttttggt ttatgttttg 72960 ctcactgtct gcaattctatgaatactatc caattcaact tattacatgt atttgtttct 73020 tctgctcttt agagttttcctatctcttat ccataaaaag aaccagaaaa atatcctcat 73080 ctaacactct tatttaacaataaacaattt ttaaggcagt aatgtaacca atccctcagc 73140 taatttttaa aaatatacaatatattatgg ctgacttcta ctcctggtta cattactaat 73200 ttttaatggt ctaagagcaaatcacttaac tctcaaggtg ctgcagtttt tgttatctac 73260 tgaaaaggta gaatattagtgtgaccaact tacctgataa gggaaaattc acctttatat 73320 aactgaaaag ttaaagcggtattcaattat gggagaaaag tttccctcca aacactctac 73380 caatataata atgtcctttggaaatacaaa actactaaat gaagccacta gtatatatat 73440 agctcacata ttattttttttaagctataa agacagattg agaaatgact aatttcctta 73500 ttcaacagat attccaaaaaggagcaaatc agaaacacaa ggatagaaaa gcagaaaata 73560 ttttttacta gcatatttacaggtggcttt ttaaaaaaat ctcaatacaa tcacaaagga 73620 aatccatcca tcactaacaagtgcacacca aataattaac actgttttct agaaatagag 73680 ggttttacaa accttatttcttacctaatg tattctaagg cacagcctta aagatagcta 73740 aagctatttc cctcactaaaaaatctgcta ttatatctgc ttactcacga catagaaata 73800 actttactct gattatcaatcaagcatagc atcacattcg tgtaattttt tcacaaacca 73860 tgtttcacaa ctgttttgtgaaataattta tttggcaaaa taattctgac cacatgtact 73920 aattgtattg ttttatggttcattactaaa gatttctata attggttttt taaaaaaatt 73980 taaacatgct gaaatagtggaaactgtttt ttcttttgtt ctttgttgaa aggtatctct 74040 aatatacaga aagtagacatttaaaaaata tgactacaca aactgcagta gttgaggaga 74100 ccttaatact tcatacagtaaatagaaaca ctgctcggta agttgtatgt gatatattaa 74160 aacattgtaa ttcaaatacttggccaatta tgttaacatc taagaaacaa aatgtgaaga 74220 gaagagtata aactcaaatatttaatatac taccaattga ttaaaagcaa gaaatgcttg 74280 attctttggc cttaattttaaaatcagtgt acttgagtaa aattctattg tgctagaaga 74340 ctattaaaca agtacaataatacgagtatt tatttataat ttcttcacat ggttttccaa 74400 gtattttttc ttctctatattgtatcttca tacttgtgaa tttccaaagt ttcactgcta 74460 aaactgataa aactgtatcagttatcacaa tgtacaggca ctgtaatatg cacaattaat 74520 tttcttttaa attcagcatgtcaataaaag tgtggaataa atcattcttt attgatggga 74580 atttaaagtc aaaataatgaaccaattttt aaatggattt cctttgtgac atgcagagta 74640 cctttgtcaa aaagctcccaaatctttagt aggtataaaa tgaagagaat gataattacc 74700 atattgaaat aagatcgtattttgactcct cttgccagat cccacactat cacgtttcca 74760 tcatgaccag cagaaaagagaactctagga tcgaacgggt gtggttcaag aacaaatacc 74820 tcatcttcat gaccctgaaatatttttgaa gtgtcaaaga atcatagata ttaaaaaaga 74880 aagaaaaaca aacataatgaaataccaata tggcactatt tctagaaatg gagttttaag 74940 aagtattaaa ttggcaaaaatcttcaaatt tgtcatgtat atataataat gaaactgagc 75000 taatatcatt gtccagggcttggtggatgg atcttttcat attaaaaaaa cagcaaatat 75060 ctactatata tttccaagccaaacctgttt aactgcactg ttaaaattat tcccaatcac 75120 tcacaaagcc gttaccccagcaagcaagag tttttagcta acataaaaga ctttattcct 75180 caatgagaat gtttcattctatagtcagct tcagttatat caaataaaga ttagaatttt 75240 ttctcaccat caggacatgaattagttgac cagtgtaaga attccaaact ttcagagtca 75300 tgttattaac tgcagttataactgtattgt catgtcgatc ccaagctacc atagtaacct 75360 tcatttttgt gattttatcttctattcctt gaaggttttg gctgaaagtg aggaagtgtt 75420 ttacactgac tattaaaatactgacacaac aaaaaccaaa acatataatc tataattagt 75480 atttatattc actaacataataactatcac ttaacagtaa ctgagaagtt tgaatcaaca 75540 tggaatgatg gtaaaaatccctgcactgag tcaggaaatc caggatttcc agaattctag 75600 cacttctaag ccattagtaagatgatcttg cataaatatc actgctataa ctctatctag 75660 atccaggaat tctgtgccatgctgctcact ctccatcttt tactgttgct gtcatcccct 75720 gctgactgtt ctgctttcccatccatctga gatgactaca cacaaataca agtggagaaa 75780 aatattaaaa ccaaaataacagctacaaca cgcagtttaa tttatcttgg cttgaagaaa 75840 ccattggaca taaaatattgtccctctgtg ataaacgaaa cataatatgt tctggtttct 75900 gaaaaaaata tttaaagttaaaacttttct tacagtactt ttatcatctc cttaaaaaaa 75960 ttaatgcaat gtcctgaaatatgccaatga atcatttcat aaaaatcaac actgctcatc 76020 tccaattgta cctctagttatcgcagaaaa gtagtaattt taacatgata tataatttta 76080 taggctgaga gtcaccaacctgcactataa catactttaa aaaatcaata tatacataat 76140 atttcaaatt tgacctcttaccctgctgga cgagtagcca tatccaacaa aatgctcttc 76200 cactctcttc gtttaaattgccaaatacgt gctgtcccat cacgactgcc acttacaaac 76260 ctgtattaaa aggaatccgatcccccaaag aaaaatcata catgctttac caaaatgcac 76320 ttttcccaga gatcttgtttaaaaagacag cattcatctt tatttatgca gcattctaat 76380 aacttctgaa actttatgggctttttagaa ttttatatgc aaacattcca attttcatgg 76440 ctaggtcaca aaataacattttcaaaagtg attcaaggtc actatgtact accctagaaa 76500 taaaatcgac attttccaaggaaaaaacaa tgattttctt ctcaatatta aagaatctga 76560 cttattctac tcaaggtattagaagtagct ttatttcctt ttataacaag aacatgggaa 76620 aatttataca atatcatcaataaacaggtc tgccttaaat attatactgt gatacatttt 76680 caatctatac caaaagcttctctacatttt gaaacatatc tggaatatat agggtgattt 76740 aaaaagcagt aattactaaaagtgtccaag tatactaaca ttattacaaa taagagaaag 76800 acgtgcctat gcatgtgaaggctatattca cttttaagta taactggtca agatctttta 76860 ggtaggtgat tatttcctatacagcttcaa ataaaatctg atgactaaaa ttgtctttat 76920 ttcataattt taaaattagaattaaattag acaaatattt tacctgttac tagtgttgga 76980 aaactggata ctgtcaactttgtcctatat ataaacaaat aaacaaaaaa gtgggtgctg 77040 aatataaact cttggactcacataaattat actcatctaa ttcttttcac caatacttac 77100 agtatgaaac tccaattctgatattttctc tggctgacct gatccaaaaa aataaacccg 77160 aataatatga tctgtgcttcccgtcgccag aaacattcca cctatgaaga ataacagcaa 77220 ttgttaagaa gtaaaacataacttcaaaat ctctgaaaat tagataataa aatgtaagca 77280 aaattacagt atatactgaattaatatttt actccaaaac cattcacatt tatcctaaat 77340 atataacaca tctaactggaatttaagaaa gaagtttatg aatatatctg actagaatga 77400 atttttcaat atttatagaagtaaagcttt gctcaaaaaa taatttcact aagtgaatat 77460 ataaccatac catgttaaaattatcagtca ccttcactag aaaatatttc tctcgcaatt 77520 ctgctgaaat ttttctgttgtctcatttcc catgtgtcaa aatcttatca aacttttaag 77580 gcccaactcc ctcagtaacttttctttaca aactttgcaa ttaaatgagg ctgctctctt 77640 cagaactccc ctaagactttgttttgtagc atattcattc taccttgcat tacagttatt 77700 tgtatatgca gtgtactcaagagtaacact cttccacagt attgaaaaca atacctgtat 77760 ataataaaat atttaagtacttttgctaaa tgatctaccc actaacccct taaaaaaatc 77820 aaattgtcct tgaaaaaggagtaaaaattc agagtattct ggatgcatgt atgatgccta 77880 tatttgtatg actactacaaggaatactga atccatggca gtggcactga acatctagaa 77940 gttagaaaat gaacatgtttggatattagt atggcaaaga cagactcact tcattagttt 78000 gctatccctt atctcaggtaatactcctat ccacaattat aaaatgagcg gaaaaagtaa 78060 aactgaaaat aaaggtaggaggaacaggta ttagacacta tttggatcta ctcatgtttc 78120 atttaatttt cttatcaatttactacaaat aaccagattt tttttataac ttgtttaaaa 78180 ataccctaac atccattcaaaatgctgctg cataaacaca aatctgaatt ggaatcttag 78240 cactgctata caatcactttttaaagtgca aataagaaca atatgtagcg aattaactga 78300 taaagatgta caaatatgaatcaaatttat tttacttaac tatagaatac cttcaaaatc 78360 catgaaaaca taaaccagatttaaaatacc attcttacaa tgaaacaact atttaaacat 78420 tcattcttta acagggtcgattttgaaact atttattctc tcctactaga acattatagt 78480 cttcttaaag aaaaacagtcatgtgattat ataaactaaa ctcttgcata aatgaaatat 78540 ttctaagtta gtttataataattctcagtt acttattagc tctggcatat gtataagaac 78600 atgattgata atacaacagtaaatattttc ctaaatatta cacactccac tataaggctt 78660 ctaaatgaac aactttaagtcgaaaattag aatgagggaa acttaccagc actaaaagaa 78720 gaacagatca tttgaactccaggccgaggg cgctctgtaa attttgcagg tcttgggctg 78780 taatacaaaa aataaagaattaaaaatatc ctaaaggaac cagtagcagc agaaataatc 78840 tgtttcaaaa aataatcccagaaggacaaa attaagaagc aacagatggc tcccttccta 78900 aaaacaactt agaaatcattatgtgtcata aatcagaaga tcttgtagaa attctagata 78960 tagattttgt aggagctccttattacacaa caatacgtac atggaacaat tccaaattca 79020 ctgtcacacc agacatgcagttactagtta cacttacttc taatcaaatt taacatgttc 79080 tcagtttttc atatagaatagcaacgtaca aacatataag gaactaagct attcgcaaac 79140 atgaatacat tagcaaaataggtgctgtct gtgccttatg tataccatca ataactgaac 79200 tttttcagta ttttacattaattaagcttt tcccttcttt gacctactaa tgtgataaaa 79260 catgtctttt aagaccccaaaaagtaggga tattacattt aacctagtga aaatctgaag 79320 atactttgac tcttacgtcaactacaatga atgctcattc aaaatagcag tctacagaaa 79380 acaggttaca cacagctgtatttacattaa ttgcctaact gtattacaga ttacatattt 79440 tatatcaata ctactgatattaaatgttta atgttacagt caaccaatta gagaaaatga 79500 agatttttat catgacaccagctctaatac atttaacaat gtgtatgtaa tgttccaata 79560 tactgattat atttgaagccctacttactg tacattttgg catagttctt ctacactatt 79620 tgatgaaatg caaaaataattagagcttaa gcctatataa ctttcacaat atataacaaa 79680 tttagagcag ttttagttttgtgatcattt actggaaaaa agtatataca taaaatattt 79740 ctgagctata ggttggtgcaaaaataattg cggttttgct tttttttaaa aaaaagcttt 79800 ttaccattaa aataatggcaaaaactgcaa ttatttttgc accaacctaa tatatattct 79860 gagcaaagag aattatcttttttactgata cagaatgcaa caaaatgtta agaatttaaa 79920 aaataagttt gtaaatagttttacattagt atttacagca aattctatta atattcacag 79980 gctctaatgt aacagatgagcagaacaaat ctcatttaga gagacagata ttagaacatt 80040 cttaaaacct aaacatttattcagagcaaa attaactgta atttaagtaa attaatctga 80100 attatgaagg caactaaatgcattgctttc attactacct tatggattat agctctagat 80160 tttttttaat ttttggtacatctgctcaca taagttccaa gcaaccattt acctgaaact 80220 cattacaaaa atatgcaaatagtcctataa actaccattt ttaaaaggtt tttattttag 80280 aaaggaaatc agtatattgaagggatatct gcactcccat gttcgctaca acactgttca 80340 caatagcgaa gatttgtgggttttttggtt tttgagacgg agtctcgttc tgtggcccag 80400 gctagagtgc aatggcacaatctcagctca ctgcaacctc tgcctcccag gttcaagtga 80460 ttctcctgcc tcaacttaaaattttataag ttaaattaca gccaaatgac aaaagcaatg 80520 aaattatatt ttaaagtattaaattagtgt gacaatgtaa gtaattatgt gtttgtttac 80580 ttgtttaggt ttaaagcaaatcagtaaggt tagtttaatg gaaaacacac acacatagat 80640 gctttggaac ctgatggaccatcatttgag tctttgtcat tgctaatgtt acttattttt 80700 agacacttct ctttacacactggtgaatta ttttgattaa ccaataaatt taataaagca 80760 ctacaagtta cttttttattggagacagag gctcactctg tcacccaggg tgaaatgcag 80820 tgacgctatc tcagctcactgcaacctctg cctcccaggt tcaagtgatt ctcatgcctc 80880 agcctcccaa gtagctgggattacaggtgt gcaccaccat gcccggctaa ttcttatatt 80940 tttagtagag acaggagttttaccatgttg gccaggctgg tctcaaactc ctgacctcag 81000 gtcatctgcc tgccttggcctcccaaagtg ctgggatcac aggcgtgagc caacacgccc 81060 cgccacaata gtgaagatttggaaggaacc acagtgtcca acaacagatg aacggataaa 81120 gaaaatgtgg tacttatacacaatggagta ctattcagcc ataaaaaaag aatgaaatcc 81180 tgtcatttct aacaacacagatggaactgg aggttattat gctaagtgaa ataaggcagg 81240 cacagaaaga caaacatcacatgttctcac ttattttggg gatctaaaaa tcaaaacagt 81300 tgaattcatg agatagtagaggatggctat tataggctgg gaaaggtagt gggaggaaga 81360 ggagggaggt ggggatggttaatgagtaca aaactaatag aaagaatgaa taaggcctag 81420 tatttgatag cacaacagggtaactataat caatagtagt tatacatttt taaataacta 81480 aaggagtgta attggataatttgtaataca aaggataaat gcttaaaggg atggagaccc 81540 cctttaacac catgtgattattatgcattg catgtctgta tcaaaagatc tcatgtaccc 81600 cataaatata tacacctactacatacccac aaaaactaaa attaaaaaat aaaaagattt 81660 tatattttta aagggaaaaaacaagtagct acccataatt tgtttttaga tgcattattt 81720 gaggaaacat ttttaaaaagggccttgggc cgagttcagt ttctaggtct atcacttatc 81780 aagagtgcga ccttaggccaagttaacatt tctgtacctc agtatcctca tctgtaaaac 81840 aggggtaaaa cggaacctatttcagagttg ctgggagaat taaatgagtg tgatacatgt 81900 aaagtgctta gtacaatgtccaatatgctc aataaatatt agtattttta ttaggttcaa 81960 caagttctag ccaatccttcaatgactaac tgccacttag tttggcacag tggttaaaag 82020 gggtttctga cattatacctctagtagtat ttaaatcctg gctccagtac cacctgctaa 82080 caatgtaacc tgctgtgccccaggtttttc ccttatctgc cccagagata ataactgtac 82140 ctttctcaaa gggttgttatagggattgag ataacaaatg tgaaatgctt agtactagct 82200 tggcagacta agcgcctaataatcacaaat aaaaatttgt aatcatcata ttatatgcat 82260 attttaggat tcctagtctctttacaccta agtctaaata tacttggaca gcttcctcct 82320 acccagagac ctctggagctagcttatggt tcacttagcc acttagacta cccatttaag 82380 aaacagcatc tttgctcgtgagttggtaat acacacatac aagtgaattt ataaagatat 82440 ttgagttccc aaagttgaattgattcattc aactaatgca gatgcaggat ttctaaagtc 82500 atttccccca gcagaatatacaaaagcatt atagctaaat acaatttttg cctttgatta 82560 ttaattaaat cctatgtgacataaacagta taaatctata tcctgccaaa tttttggcag 82620 ttttcaacta tgtgtaaacacataaagaaa ataggtgttc caaggcttat atctaaagag 82680 caatggattg ttcttgtttttgtgttttta ataagacagg atcttggccc tgtcgcagag 82740 gctacagtac agtggtgagatcacagctca cttcagcctt taactcctgg gctcaagcaa 82800 gcctctcacc tcagacccctgagtagctgg gactataagt gtgtaccacc atgtctggcg 82860 tttgttgttg ttgttgtttgtttgtttgaa tttctgtaga gacaagatct tgctctgtta 82920 cttaggctgg tctcaaagttctgaactcaa gtgatcctcc ttccttgacc tcccaaagtc 82980 ctgggattag ataagaatgagccactgtgc ccagccagag tactcattct tatgcctgaa 83040 ctctgaattt aaaaattttaagggacaaga ataggaaaga atataggaat aggaaagaat 83100 attacttata aatacctagaaaaaactttg aagtccaaaa ataaaaaaat tactaagttg 83160 tatataacaa ctctattgaacataatgcaa gctattaaaa tacatataaa tatctatggt 83220 aaaatattaa gaaaacaaaattatatatat attcctaatt atatctatat aaaaacattc 83280 atggagaaaa aatactgtattagggtagtg gtttatatgt gattctacat aaaggttctg 83340 aaaaaatcat ttatatggacaagcttactt ctcaagcatc cagaaacatg aaatgttatt 83400 gtacttagca ataaaatcctcaagaagcac aaataaggtg tgagtttaat tctgtaaaac 83460 attttctgtt cctatcccaatttgaacatt gctaatcact ttttcttctc taaaacaata 83520 agacaggaaa agagaaaggtatccccatca ggtccatgag gaggttaaaa aacagtagca 83580 acaattaaca attaactattgctactgtcc atatacatca gtaaaatatt tcaactttta 83640 tctatctaca gaaagactttaaatacgagg gatgcaactg aagtgaagtc aacttgcttt 83700 gtccaaagaa ccatgttttaaatcacaatc ttttttcaaa tgaagtagtt ttgttactcg 83760 agctaccatg gcccccaagctgccataaga accactctac aagaatgttc atatacatga 83820 agttaaagaa gcatgtgttgcattacaaac aattatctaa acactactgt ttttaaaata 83880 acaaaggcat acatatattattttattaaa taactcaact tgggttgcta atttatacat 83940 agcagtcaga gataattactgatatatacc ttctaatctg aatgactttc caccccgagt 84000 ggcagaaatg gccatttcaacactgtgaaa tcaactgaat aatcaattga atacactact 84060 ttcttgttca aagactatccatggagcaaa tacactattt cctctcccca ctacatccac 84120 ttaaaagata tggtatagaggctgggcacg gtggctcatg cctgtaatcc caacactttg 84180 ggaggccgag gtgggcggatcacgaggtca ggagatggag accatcctgg ctaacacggt 84240 gaaaccctgt ctctactaaaaatacaaaaa acttatacgg gagtggtggc gggcgcctgt 84300 agtcccagct actcgggaggctgaggcagg agaatggtgt gaacccggga ggcagagctt 84360 gcagtgagct gagatcgcgacactgcaatc cagcctgggc gacacagtga gactccgtct 84420 caaaaataaa taaataaataaataaataaa agatatggta tagaaagcat caaagggcag 84480 agaagtgctc tagtcctggccttgccaatt tttaaacata gttttaacta tgggaaagtc 84540 atttaaccat ttcagtgcccttaatccaaa gataatacta tccagccaac ttgttttgat 84600 aaaccgaagt attaatatgggcgaccgcac aaatgcaaaa tgttattatg gggagggagg 84660 ggaatacatc tatctaccttgatgcagttt agtgaaactt caatgattct gtctccctac 84720 attttcctag atctaaaataaaatctaaag tttatagatt cagtagcatc aataattaaa 84780 attattctaa agaacagcattagaaattct taagattaag ttctgagcat caaaagcagc 84840 tattaaaact atgcagcacatagaaaggag tggtaataaa acaggtaaat gctgaaggaa 84900 agagctagga ttaggataaagagaaaaaaa atgtgaacat gagaaacttt ctttgaaaca 84960 taaaaaaagg ggaggaataaaaataaaaca ggttagtaaa gagccaaaag aggatttcta 85020 ttatttactc aaggagaaaaagtaaatgta ttcctattgt cgactacttt atacttttgc 85080 aatttcactc attaaactaaacacatttaa tctatgaaat aaaatagaaa ctgactttat 85140 tttaagggtt ccagcatcccagagccaaaa acaaatagtg ccatctgccc cagtagaaga 85200 tagatatctc tttgagccactgcacaatgg tgagaactga aaagacaatc acagaaaaaa 85260 aatctttaca agagtgacacagtcaaaata aaatctactt tttgccatac aaatagcaac 85320 taacaacaac agttagaaaatggcaagaat ttaccaaggt tatgttattt aaagtccata 85380 tatttataaa gaaagcagacatactcctgt cttcatttta gttggcctta tatactggat 85440 tataaaggtg attataaaagtaacttctta aaatttaata accaaaagtg acttcattaa 85500 atttacttta cattataacaacaacaacaa caacaatgta tagggattaa gacaattacc 85560 tgtagtgatg taatagatgcactatggccc tgaagaacag ccaaaggtgc acaggttcga 85620 agacaccaga ctcggatcattttatcacaa cttccagctg ctatcatggt attctcatag 85680 tttacagcca tgtctgatatttcagcagca tgtcctctta aggtagctaa caacctccca 85740 tcatctgttg cccatattttcacaagacag tcatcagaac ccttaaagta agaatggata 85800 ttaatagaat taaccccataaattttaatt caaaatctta acactgataa atctacctgt 85860 tctgtccact tctgaacaagtatattttta aataccaaaa agtgttaaat acttgtgtta 85920 gcttacacaa agctctttattaaaccactt aaaaagagca cttgtgtact caccagcaaa 85980 taagacaagt gggataagataattaatatt tacctttggt tccctatcta ctatcaaagt 86040 accctcaatg tggatttctgtaaaagaaat tgaacttctg aaataaaaaa aaaaaaatca 86100 tagctgcaaa acaaatgcaagctacaatgg tgactaatat tatctatttt gttttgtaat 86160 acaaaactaa aagtaagcttgtttggggct ttttctctca ggaagctgtg agtttcctat 86220 cactgatctt cagctaaaaacatgacatta tctaaagcca gttatcagaa aaaaattaat 86280 ctcatctgta tgaagtcaataaaaatacat aattacttgt ttactctgcc atagtagtgt 86340 aagtccagaa agaaattgtaaaggatatgg agtttcctat gaatatctat atttacaaat 86400 gaacattccc attttatatagccaaaatag agatagaaca ttcagactct atttttattt 86460 tttattataa taattttaaatatataagaa agtagaaaga atagtatcgt taatccccat 86520 atatctactt cccagattcaaaacttaata tttttgccac attttctagt ctttaacaca 86580 aggttaaaag agaaaacacacacttttgca aaattactga atattttaca ggatacagtt 86640 ttactaaggg ttcatgttagaatgcttaac gaccttccaa tctaattctt aaagaaacac 86700 cttcatatct gacattagaaagaactcaga ggacctatgg aggcatataa ttcagacaac 86760 tttctgcatc atagtgacaataaatataac atataaatca tcatactgac aataaatata 86820 acatattaat gtttccaaacagagtatgtt aaatgctgta tcttaaatca gactctgcca 86880 atgataccta aaacaccccccaattaacga taaaaccagt tcctctgatt aagctttgga 86940 gtaaaataaa tgggttactaaccactataa agaccagtaa aacttaactt tggtcaacta 87000 tccatattgt tgtctagtattcttatcaca tacccttaac ctcacctcag gctcttcatc 87060 tataaaatac ggaggttaaaatggatggcc tttaaagttc cctaaacctt taaaattaag 87120 cgattcatgc attcatttatccctttgtct tgtgactatg tgacaaccac taaagatata 87180 agaatgagat ataaagacacagtattcttg tccttgtgaa gcaagacaga agaatgtaaa 87240 tgtgataacg tcctatgtattatataggac atataaacac ttatatgtcc taagtgttta 87300 accactgtta atcagcagagattcaaacaa ggaaacagtc tactttttct gagagatgca 87360 gaggtacggg gtggaaaggaacccagaagt ggtgatgctt gaatagagtc tcacgcaaga 87420 agaggcaatg taatgtagcttagaggacag ccttcagggt caaatgcatg actttggaca 87480 tgttacatac acttcttgtgcctcagattt ctcacctatg cgtacctcat aggattgtca 87540 caaaactaaa tgagggtgaagagatgagac agtgtctgac acatggttac agctttatct 87600 tctaacactg cttttgctggtgacagtatt catattctta ttttaataat atcattatta 87660 ttattttaaa aagagcattccataatgtga ctataaagta tggtcaaaag catgaaaatg 87720 tgaaacaatg tgagtagttcatagaactgc aagcagcctg caaggtaatt tagagtgtga 87780 ggtgaaggca taaggatgaaaaagtaaaaa aaatttgtga aaggcctttt acggtttact 87840 aagaaaagtg gtgtgtaatgagggtcactg aagatatcaa acaggtgagt atcaggatca 87900 tacttgtgtt ttctaaagatcatcctggca tcagtgtgaa ttaggctaag acagaaagga 87960 gaccagctga aagttgttaaaatagtatgg tcaggagaga ataagtggta acacaaatta 88020 ttatagcaaa aaagaataatcaaagacatg gttataacag ctgtttgggg aataaaaggg 88080 ataaggagca catcactgattatctgttgg aagtgaagga agagctgtag cagactatga 88140 ctcccagaaa gctggtctatacgcacatcg gaaacacatt agggatttgc tgagtaaaaa 88200 aaatgcttta gggcattcattcaaattaag ttctctacat ttcacaaatt gaatcaacat 88260 attcactaca tttggttatcttcccaaaac tgaagcaatt ttggttctca cctgcattca 88320 gtacacaaag aattttaagtacactacagt aggtagacca tataacaaaa gtaaaatcat 88380 gacatcatgt tatgcttcacaatactgata caattcatat cattcttatg aatctttgaa 88440 taagagtgtg ttttacattccactataaag atgcttcaca tatttttcat gttaacaaat 88500 aaaaacacca gtcttttgaccaaaatgtca gttttaatga aaggagcaat ggtaatctgt 88560 gacctaaaat taacctccagtgactttcac caattaaaat gtaacaggaa gtcctactat 88620 attcctactg ggtttatcatttagttatct taccacttta gtattgcttg attaaatttg 88680 ctctttttag acaagtgctgaaaacaaaca aaaatgcata tgcttccctc tgagtgcata 88740 ttatctcaat taacctttcttttcttccat caaattgcca gagagagaaa tttttgacca 88800 tcctttcaca aaaatctctccattatcctc ttccatgacc cacagaagtt tgctgcccct 88860 acccctaatt ctacccctcaggactcccgg aagattttcc aacagaactg caagcattct 88920 taagcaattt ctatctcatatatcatcgct tgtgataatt aatttaactt tatggaaatt 88980 tgaaacaaaa gataatctgagcatgaattc aatgaaactc ttttaagatg actatacaat 89040 atacaagtac tcaaaaataattgactagaa gaactgcaga ggaaaaatta aatgtattgg 89100 gaaaaaatgt ttaaagcactataaatgtgt tttattttat tatttataca tttccttatt 89160 tactttgaga cagtcttgctctgttaccct ggctggagta cagtggcgtg atcatggctc 89220 actgtgacct ccacctcccaggttcaagtg gttctcatgc ctcagcctcc tgagtagctg 89280 ggattacaga tgtgcaccactacacccagt taatttctgt atctttacta gagatggggt 89340 ttcgccctgg tgaccaggctggtctcgaac tcctggcctc aagtaatcca cccaccttgg 89400 cctcccaacg tgctgggattacaggctata aatgtgtttt aaataaatga ggaagaatga 89460 attaaaaatc gataaatatgattattttaa aaaagaccaa aatgtctaac ataatttgaa 89520 cggatacact ctcttttccataagcctacc tctagttcca cgaatgttac taagatcaat 89580 aagccaaaga gtaagatattatagtctttt gaccaaagaa aaataaaatg ttaaaaccaa 89640 gttatggata ttaaaaataatgttacgtaa atggtgaaaa ggggcaatga cataagatat 89700 acctcttcta aggtgtatgaaagaaaagga agtagggaga gatcatgtaa cctcagcaaa 89760 aacaaaacaa aacaaaatctgaggattaaa agtgagaggg agagaacaac aagcgaatga 89820 actaaaaaag tgaagaaagtttggaaatgc agtggaataa aagcagtaag aaaggtggaa 89880 aaattctgca agcaacaattaaagacctgc taaatttaaa tagcatgatg ttagaaatac 89940 ctcaactgac atagttttttcagcaaagct ccaatactca agggaaaact aagtagtcat 90000 ttcttttcag taacatctcaatgttgctgg ggattgctgc tcgggctagg aattggcaaa 90060 gtaagaaaac ttgaaagtacaaagtgtaag tgaaaataag tgattatgct ggaaatgttt 90120 tacctaagaa tgataattgagttttaaatg cctgttaaga gtttgtattt aacctgctga 90180 ggtagtcact agacaatttgtaagcagaca agacatggtc actatagtat tttagccaga 90240 tcctgctaat gtttatgtgagtaatagatc tgaagctaca agaagaggtt taggttagag 90300 atagagatct gggtgttatcagtttatacc atagtagtca aaacaatgat agcagatgag 90360 attacgaaga gagaccacttagtgtagatt tttatctgga aaactatgaa caggttttaa 90420 gaaatccatg gggtgggtacaaaatttaaa atctttttta taattcattt taaaatcaaa 90480 ttattgtgct attgtttaatcacaaagata agagagtagt aaatcacttg tttcattttt 90540 ctttcttgtt tttttttgtttgtttgtttg tttgttttga gacgaagtct tcctctgtcg 90600 cccaggctgg agtattgtagtgcgatctcg gctcactgca acctccgcag cccaggttca 90660 agagattctc ctgcctcagcctccagaata gctggaatta caggcgtccg ccaccacacc 90720 cagctaattt ttatatttttagtagaggca gggtttcacc atgttggtca ggctggtttc 90780 aaactcctga cctcaagtgatccatctgcc tcagcctcct aaagtgctgg gattataggc 90840 atgagccatc acaccaagcctcatttttca ataatgtaaa atggttataa ttactgcgaa 90900 agagtgctca ttaatattatcatttgttta tatcaaactt agcataagct ggaaaaatct 90960 caagcaaatc tgtatagcccttagcttatt taaatcccaa aacaaaatga gacaccaaat 91020 ttacagggtt tctttttaagtcaagacaat cttgtcatca aaggatgaag ccaaggaagc 91080 taaaagagta catctctatacttgaaaaca caacagcata gatattattt atgagaaagt 91140 gtgttgagaa agggtgggaattaaacaaaa tttacatttt tccaatccta acaatttggc 91200 ttcaagtact ctaaaattagcttagtctac tgccacacct gaaaaaaaca cacatattat 91260 gataaagaaa tgtgccttaaaaacagtcaa cacacttctg cactttagga tgaaggaaga 91320 aaacagcatc agatatttactttgtaacca ctgttatttc ttctagtact tttacagtat 91380 ggaggtaatg gtaccaattacttttccttt cagcatgcag ctggatttct tactataagc 91440 aattagtatt tttttctgtatatccaaaaa aagttctgat tttgtaaatc cctttaaaaa 91500 cttcaacatt cttcaaaataaaaagtttca gaggcaagac tcaaataaaa acaaatatag 91560 tcatacttcc tagataccgcaggctcagtt ccagaccact gcaattaagc aagtattcca 91620 acgaagcaaa ccacacaaattttttggttt ccaagtgcat gtaagagtta cgtttacatt 91680 atgctgcagt gtattaagtgtgcaatagta ttatgtcttt aaaaaatggg catacattaa 91740 cttaaaaata ctttattgctaaaaaatgct aattatctga aacttcagca agtagtaata 91800 tttttgctgg tggagggctttgccttgatg ctgacagctg ttggctgatc agggtggagt 91860 tgctgaaggt tggggtagctgtgacaactt cttaaaataa gacaacaatg aagtctgctg 91920 catccattgg actcttcctttcacaagaga tttctctgca gcatggaatg ctatctgaca 91980 gcattttacc cacagtagaacttatttcaa aattggagtc agccctctca aatcaagcca 92040 ctgctttacc aactgagttcatgtaatagt ccacatcctt tgttttcatt tcaacaatgt 92100 tcacagcatc ttgaccaagagtaaattcca tctcaagaaa ctactttctt tgctcatcca 92160 taagaagcaa ctcctcccccatttaagttt aatcatgaga ttgcagcaat tcagtcagac 92220 cttcaggctc cactactaattttagttatc ttgctattgc agttaacttc ctccactgaa 92280 gtcttgaacc cctgaaagtcatccacaggg gatgcaatca acttcttcca aactcctgtt 92340 aatgttgaca ttctgacctcctcccaagaa tcacgaatgt tcttaatggc atctagaatg 92400 gcgataataa tcgattctcaattacaggtg aaacaggagg ttttcgatgt actttgccca 92460 gatccatcaa atgaattactatccatgaca gctacagcca tatgaaatgt atttcttaaa 92520 taagacttga aaatcagaattactccttga tccacaggct gcagaataaa tgtattgtca 92580 gcaagcataa aaacaacactaaccaccttg tatatttcca tcagggttcc tgggtgacca 92640 ggcatcttgt taatgaacagtaatatcttg aaaggaatct tttttttttt ctgagcagta 92700 ggtatcaaca gtgggcttaaaatattcagt aaaccacgct ataaaaagat atgctgtcat 92760 ccagactttg tagttccctttacagagcac aagcaaagta gtttagcata attcttatgg 92820 tcctagaatt taaaaaatggtaaatggaca ctggtttcaa cttcaagtca ctagctgcat 92880 cagccctgaa caaaagagtcagcctgcttt ttgaagcttt gaagccaggc attgacttct 92940 ctctaattat gaaagtcctagatgatgtat ttttccaata cacagctgtt tcacctgtaa 93000 ttgagaatct attgcttagtgtagcaactt tcttcaatga tcttagctag gtcttttgga 93060 taatttgcgg caactacttcattagcactt gttgcttcac gttgcacttt tatgttatgg 93120 agatggcttt tttccttaaacctcgtaagc caacctctgc tagctccaac ttttcttatg 93180 tagcttcctc atctctcagccttcacagaa ttaagagtca gggtcttgct ttggattagc 93240 ctttggctta aaagagtattgtggctagtt ttgatctcct atagagacca cttaaacttt 93300 ctctatatca gcaatgagctctttaacttt ctcatcattt gtgtgctcac tggagtagca 93360 cgtttaattt ccttcaagaacttttgcttt acattcacaa cttggctaac tcttttaaca 93420 tgcattcctc actcgccttaatcttttcta acttttgaat taaagtgaga gacctgagac 93480 tcttcctctc acttgaacactaagaggcca ttgtagggtt attaattgga ttaatttcaa 93540 taggcaggcc caaggagagaaaaatgggga agggccagtt ggtggagcaa tcagaacaca 93600 tgcaacattc attaagttcgccataagggt gcaggtcatg gcaccctaaa aagacttaca 93660 ataggaacat cagagattatagatcaccat aacagttata ataataatga aaaagcttga 93720 aatattgtga gaagtatcgaaatgtgaaag agacaagact tgagcatatg ttgttagaaa 93780 aatgatgctg acagacttgctttactcagg gttttcacaa atatacaatt tgtaaaaaat 93840 acagtatttg caaaatgcaataaaggcaca atgaaacagg gtacgtctgt attagcattt 93900 ttcataaagc ctaggcagtgtctagtaaca catttgactt taatgttctc atgaagaaaa 93960 gttccacagg tctttatgacgtggctttct actgttaggc actttggtat taaaattatc 94020 ctcaaaatcc agaaaaaaatggcctacgta ctgccatgaa aacttcaaac aacttcagac 94080 acagggccat gaatcacttcaattcgatgc agaaaccaaa cagcacctaa agtctatgcc 94140 cccaaatttt aataatttaatgagtttcca gaggttaagc ttcaaaaggc ctaattgaac 94200 tatttattta tttaaagaaaagctaagttt cagaacaact tgatagagct ctttctggta 94260 tggcttattt acagatactctgactacata aatgaaatac aggcctttct atgcaaggcc 94320 aagaagtcaa tttaggcccagatgttgcaa aactatgaag tagacaatta gagaggacaa 94380 ttctgttcag taataaagtaatttacagga agcagcataa atgacaagga atggttgaat 94440 tctctaagtg aaatcatgccccaaagagtt aaagaaatca acgactaaca ttgattaaca 94500 ctgaatgact aatattctttgagtgtgcgg gatggcaact aagaaacaac ttgtccaaac 94560 actgaaactc cctctacttatgagatagaa ctggctgaaa tcagttggaa ccaagatggc 94620 caactggagt ctgcacagaacaagcttgct gacatcatag cctgactatc taccacattt 94680 catactaact accctagaatttgcacatgt gacccatgag gtatcataat gagttaactg 94740 tgcatgccca gggacattccagacctcccc tttccttcca ccaaacacct actaatctca 94800 gaattcaccc ctactgaacctgtaataaaa atactgcctt gaaaccagca tgaggagaca 94860 gatttgagct tgacccctgagtcttcttgg gagttgactt tcaatataaa gcttttcttt 94920 tctcaaaaac ccagtgtcatagtattggct tctagtacac tgggcagcaa gccccctctg 94980 ctcaataaca caagcagaaaactgtacaca ttgggaaaca gtttacttct gttcagataa 95040 cttgagaaac cttaaaattaaaatattgac ctatgtacct aaaagagagg cataaattat 95100 acaaagatta ctactttgacatgaaaataa aagaaattat gtgatttttt aactaaaaat 95160 atcttagaga atttggcattccttgaaaac ctactgttat ctggcagagt caacaaggag 95220 aattttaatt tctcttgaggctactttaca gcttttgagt cagagatctc atctcttatt 95280 gccattagaa taagcagtagaaatgaatgc caaaaatgtt gtctgtattg tcatatttac 95340 tacaatttca ttttcctattcaagctaaaa agtaacctgc ttttctagca aaactaaaaa 95400 ttgcgtacaa tttaaatttggttcaatttt tttctaggtc atttattttc tttcttacca 95460 atctatcaga cctgtgtttcatttccctta caaatcaacc taaacctcag ggtcaaacat 95520 ttcaacacat gtctgatttcattctcgacc cttattcatc tataccacca atgaccaacc 95580 cggtgtcaat ctaaccatcacttgctctga tactgctacc aggatgccaa gaaacattac 95640 ggtaaggaat ataagcatactaattccaca acactacgaa ttcatgaatc tcctatttac 95700 tgggtaggct aagcattatcagcaatcatt tttcctgtct ctattcaata ctcttctatt 95760 gccaagcttt atcagtaatttctagaatcc ataaacaaga ctctcgccag acagaacatt 95820 tcatattgaa aagtagaaactgttaattgt ggaccaaata actacctttc taaaaagtcc 95880 acactgctat tgtatacatcccacctcctt aaatatcatt acatatcaat aatctcctct 95940 cgtatcttca aatttgctatcttagtagtt tcttcctctc aatccagttt tcctacaatt 96000 tactgtcctc taaatgaccatactctgcct cttttccatt attatcaaac atgctaaatg 96060 ctcactattg cttctaaacaacctcctatg cacttaaaat aattttgaat ttcaaacgta 96120 caaaagtttc aagaacagtacaaatgtttc ccatatctcc attaccacct ttcttccctc 96180 cctctctctc catataacatacacacataa ctccattacc attaatcttt tttctgaacc 96240 atttaaaagc aacgctgggccaggcgcggt ggctcacgcc agtaatccca gcactttgga 96300 ggccgaggcg ggtagatcatgaggtcagga gatcgagacc atcctggcta acatggtgaa 96360 accctgtctc tactaaaaatacaaaaaatt agccaggcgt ggtggtgggt gcctgtaatg 96420 ccagctactc gggaggctgaggcagaagaa tggcatgaac ctgggaggtg gagcttgcaa 96480 gtgagttgag atggtgccactgcactccag cctaggtgac agagcaagac tccgtctcaa 96540 aaaaaaaaaa aaaaaaaaaaaaagcaaggc tgctgacttg ataccccatt acctctaaat 96600 atcgcagtgt atatttttctaaaacaagga tatttcccta tgtaagttgg gaaatcaata 96660 ctgataacac taccaataacaatactggta acatccaaat ctacagggcc tattcaaatt 96720 ttgtcaactg ttttgtcaacaatgttctct tttccttttt ggcccacaaa cccatataca 96780 ctatatttaa ctgacatgtctcatcaggct ccttcaattt ggaatacttt ctcaggcttt 96840 ctctttcatg tcctcagcaggttataaaga atacaggcct tacaatctgc aggatgaccc 96900 aaaacctagg tctgtcaatgtttcttcatg accagatcca ggtcatatta tcttttacag 96960 taatcccaca aacaagaagctgtgtttttc tcagcgcatc acttctgaga acacaacgtc 97020 aacacatccc agagctagtgaagttaacat ggttacatta gtatttccaa ggtttttccc 97080 cataaatttg caatgtttgctctttaattg attagtatct ttgggggaca tattgcaaga 97140 tcttcaaact aagatcttctactggtcttt atctgctaat taaaaaataa taataataat 97200 cagccacatg aatactttggagaaggggat cccaggcaaa gtcctaatac aaagacttca 97260 agccacaaat gggctttccaagtctgaagt acaagagatc agtgtaaccg aagtacagta 97320 gcagagagga acttatcttacagatatttg tatgtatttc ccctaacaga tgctaagttt 97380 tctgcaagaa tggacattagtcatttttat atctcaaatt gcttgattca ttcatcattt 97440 gtggtatgcc tcctgtatacatcagatact ctgcaaggca ctacagatct aaaaaataac 97500 aacaaaggca aagacaaagctcacaactta ataggaaaac agacatctgt catggcaatg 97560 taataggaaa atacaatgtattagaagcac aaagttaagc ggcagtactc cacattcaga 97620 atacagacta tcatatcttttaattgtcaa gtttttgaaa gtttagttta tattaagtgt 97680 attcagtttt tcaattcccattccctcttc actgcactgc aatttcattc ctatccccaa 97740 tgctaaaaca gaacattttttggtcttagt ctgttggagc tgctataaca aaatacctta 97800 gacacttgtt aatttgtaaacagaaagtta ttactcacag ttctggaggc tgggaaggcc 97860 aaggccaaag tgccagtagatgtggtgtct ggtaaaggct ctctttgtgt gtcaaagata 97920 gtgccttcta gctgtatctttacatggctc ccctgagcct cttttgtaag ggcactaatc 97980 ccattcacaa gggctccattcttgaggcct catctcctaa agccctcacc tcttaatgct 98040 accacattgg ggattaattaggtttcaaca tattaatttt gaggggacag aaacattcag 98100 accatagcag tcatcaattaccttgacaaa cccaaaggat gtttttcagt actaatctta 98160 ctttaggttt ctgcctttcatgaaattctc atctcctggc ttctaagaca ccactcttct 98220 tttttttccc ctagcctctcaggcagcttc tctgtctcaa ttattgactc ttcttttgtc 98280 tgctttttta aaagctgaagtttcagcctt cttacattag atacatacaa gataatgtat 98340 tccattttcc aagctgaatgattcctaaac taaatcttct cacctaaatc tgagttccca 98400 ctgcctactg ggcatttctacttgactttc cacatagata tctcaaagtc aatacgtttc 98460 accttcacaa acttctccccttaaattcct accacagtaa atgacaggac tttctaaatc 98520 acagaagtga aaaaatatgtcatcctatac tcttccatct cactccctac atacaaatca 98580 gtctctcgag tcttacaaatcctattttta atctgtcaat tccatcccac tgtgactgtt 98640 taatccctga tttcttttatagatcactgc cagaaacttt ttgccaattt ctctgtatat 98700 agagttagtt tgaatccatcttctacaata atgcaaaagg gttcaatgaa aagaaaaatt 98760 ctcctcactc ttctaaccacatcaatcatt agctctccat tgccttcaga aaagaaaccc 98820 actatttagc aggtcacaaaagtatcttga ttttgtacca caccaatatc gctagttctt 98880 tatgatgagc catatttattctatgccata tccattaata cacaattgca tgttacattc 98940 tcccaaagtc tgtaattgcctttccctaag tctgcaatat ccaattcgac tcctaaattt 99000 accaagctgt tacttctctagtaaatttcc cttaccatct cctaccacaa ggttggatta 99060 ggtatcttta tctcctatggtatctcagta ccttgtacac cttctgtcaa ggttttatca 99120 cattatatca atattgtttgtttaccatct gtgaactctc caagaacaaa tactactttc 99180 aattctatat cccaactgcttaaaacagtg gctggttcat aaaactctga agttcattaa 99240 aggaatgcat aaactcattttctttattat accatattaa ttagaatcag agagacaatt 99300 tatgtttctg aaaaggggggaaaactctgc tttttatatg gcgttccatg tacttttgag 99360 tgccttagtt gtgaaaattcattaactctg cttttctccg ttaaatgtca cttaaggaaa 99420 tgattttaaa accaagtaaaaaacattaaa aggctaaaag agaattagtg aacaaaatct 99480 gacttggcaa ttatgctatttccctccttg ggtttttctc attaaaataa ttgggaaagc 99540 acccattctt aaaatactgtcatacaaaat aatgatacat tttcctaata cagaatttca 99600 ttatcaatta caatgatttcctttttaatt cttgtatacc atttataaat aagattttat 99660 ttggataaaa aataaaagataaaatttact taaatctata agtagcagta ggaaaaacct 99720 aatgactgct ttctattttgttcagtacta attatatgca ttatttcatg taatcccaca 99780 aaaatcctat gtggttggtactattatcat ctactcccct ctctctttag gtgatgagaa 99840 aactggagat taaagagatgaggtaatctg tcaaagtttc actagtagaa gtggtaaagc 99900 tgtgactaaa agccctctgatgtcaaagct gatgctttta accacagtac tgtatgcctc 99960 cagctgtgcc tgttcagaaaggactcaaga gaatcccttg gaaaaagctt tcaaatatat 100020 atacacaaat atcttagaaataaatctgca aggtcttaaa ataccaatta tataaaaagg 100080 aaatactggt tgatccattaccaaattgtt acctccaaaa ataataacag tatgttctct 100140 cacaggagtg tttcactggtcaatcatgat ctactatctt aaaggctgat tctatctatt 100200 ttcaagactg atttccataggactagttag cgtctagtct gtgcctagtg aaatgcaaaa 100260 aacactcagc acccactttattaatgagca atatgaatag tgaacatatg tgtaccctac 100320 caccacttga agtgaaaataataaaaatac aagaattttt caaaaaaata gtgccctcat 100380 atcttcgtta tttcttattgtaaggtaaca ttctgaaatc tgtaactcca aaccaccagt 100440 aaaaaattac aaatgagactgaatttagca aaacaaattc tatcacattc ttaaaaaata 100500 aacatcttta gactttggtaagaccatata aaatagtaca gtgctacttt tcttctctta 100560 attgatgtgc tttcaactaaagaaataacc aacaagcagc ttcctcttcg catattattc 100620 ttgttctcta aatcacatgcccttaaaaga aagaatcaaa tgtctagaaa aggatagcaa 100680 tttttttctg tacagagctggataaatatt ttaggctttg caggccatat gttctcagtc 100740 aaaactactc aactctgctgttgtagtgca caggcaacca tagacaatat ataaacaact 100800 gaacatgcct gtgtttcaataaaattgcat ttataagaac aagtgacaaa ctgggtttga 100860 gacgcaggca gcagcatgctgaaccctggt tcaaaaagct cttccaagtc tgtacctacc 100920 acactcatga gatagcaaaaagcacactat ttcactgcat tctccctaaa aaaattccag 100980 gagattatat gtctaattaatatcaaaaca tgtaaaatgc ttcataaaat atgataaaca 101040 aatgcttaca atccctatcatttttaaaga aagaattcct acaaggttct ttacaatggc 101100 ataactttat actgacctactggcacaata tagtgctcct ttttcattat tttaatttat 101160 tactgttttt gaaagaattctttcaaacat tagaaaaatc aaatttactt aaggtttttg 101220 agaggtgaat ttgaatatacccatattaaa cttgaatggc taaattaatt ttcgattact 101280 atttgagagc aaattactactgtaggtatg tcaggcactt cagcaaatat agagatgcct 101340 attttccact ctgaaaataatacttgatac aagagaacgt aaaaagggaa aatactgata 101400 taagaagtga tgtgcaaatgcctgaggtag attagagcca agggaaaaga aaagtataaa 101460 aatgcattcc tacatcctgctatttagctg ttttacagat gactgggtgt atggatagag 101520 gagaagtagt aggtataaataggtctcagt ttacaagcaa atttactaaa aagaggaatc 101580 tataattgtc ataactacgtaaaattcaca gctgctctct tcaaagacag gaaaatttcc 101640 atttaacttc cacttcaaattttcttattt caaaagaaat taaaaacctt gtgaatgaat 101700 gcataccttc agcccacagggtagtgttta ataataaata tcatcataat agtgtagtat 101760 tatgcttaat gaatgtagatgttaaggcac ctgaaaatca aatatttcca aaagtaattt 101820 tctcacttaa aataaagctcaaaagctttg cttttctcta ttcaacaggt tacaagaaac 101880 aataacaaat aaacaaacccaaagaggctc tataaacaaa acatcagata ttttgaagaa 101940 tgaactgtta agaataacaggtaataagag tattagatat gctcagaatt ttttagcttt 102000 tttaaaatca ctattttaagggaaatttct catagacaag caagtgattt tctacagata 102060 atataaaaag gtatattcaataatctcata caattataaa aaggcacatt taataatctc 102120 tcaacatact tagatgtccttagttcaaaa ttaaaattat tttatgccat tttgcaaaat 102180 gtcaaactgt gtatttgatatatgttgaga accatactta ttcatgatgt acaaccatat 102240 aataactgtg actgtgctgcaacatgtcat ttagaaactt tctgaatttg gataaagtcc 102300 aaatttaact aaactcttctgttagagtaa gtgaaaccac ctgaatttcc ggtttcctat 102360 taaaagaaaa aaaagcaaggttttacttca agttcaccta taagcaatat ttcctcaatt 102420 acatatatga atataaataatactttagca attacttaca gtaaatatcc gtctgccagt 102480 tcgatcaaaa gttacacagtacacagatga caagtgtcca agaattcgtt tatgcatttt 102540 catgtgctga tacactgcagttggaacaag tcgctcaagt ctgtatttcc cattcagctt 102600 ccttgaaaac agagtatccgctaccaagaa aaagaaggaa aataaatgta atctggaaat 102660 taattttctt acatgatcaccttttaagaa ttcacatact ccaatttgtc atgtgcaggt 102720 aaaaataaag aagctttctgatatatatgg cttctagtta aaagtcttta aagtaatgaa 102780 taaaaacatt gtttcacctgaaataagtca ggcactatca ttctcacttt ataacttaat 102840 ttgtaagtta aatgacctgtccaaaaatca caaagtaagg catgaagcta ggattaaagc 102900 tcagatttat ttactctctggctagtgctc tttaaaaacc taaagcattt atatgttatt 102960 tccttaaaag ctgtctatgaaatagttttt cttacaaagg cacttaaaac tggaacccag 103020 tgtacttttc ataaatcagtaacacttgaa cactcgaaat ctgacatgca gaatgatatt 103080 taaaaacatc tttataacaagtgaagataa aggaatacgt catttgcatt attaaaaaat 103140 aataattaaa ctgggaatcttgccaaacac ctgtataatg attccttctc tggaatctat 103200 tagctctccc ttagttctccctttcaactc attcattcta atcattattc aagatctgac 103260 tgaagtttat cttctgtcccaaagcttgat acattgactc cagctgaaaa tgtcctcttc 103320 catctaaatt actactgtacttattttcta tactggtaac ttatggacaa agaaggtgct 103380 caataaatat atgttgactgatctgcaggc acattattaa cctacagatg atcttctaat 103440 acaggctttt ttttttttttctaacagtga ctgccatcta cattgggtaa ttagcactag 103500 ggtttctcgg tcgaatttagccctaaagaa aactaaatat atatacaaaa tactacttag 103560 ccaaggtaca gagcccagtaattatgccct aaagttgata aaacataaat atattggttg 103620 tattatgaag aatctcagtattgcttatat tattcacatc caataaatgt ttggctcaca 103680 ctatatttcc aaccactccacactcccgct gcccccaccc caaaccccca aaaaatcttt 103740 gggcctggtg aggagatatatagcctttac aggttcctaa gcagtaatat ttcaaagaat 103800 aattacacta tgcttatatgttctttcatc acagcaataa ttttatattc tgatacagta 103860 tttctcttgc tgttagcatgtaagttctat gcaacaatct accccaacac ttgggaattt 103920 ctaaaacaag gtttgacagttgtcaattag catatttagg cttaagttgg ttatatacca 103980 atttaacaga gactcaataagtttcaatca tagcttagac cccagacaca ttttcttcac 104040 gcccaggaat ggcctggtaaaagacatcct ccaatgcttt ggctccaaac ttatttaatg 104100 caagaatcac acaaaaaccatagacatcaa ttttcctgcc aaatgagaat taaaatcatc 104160 ttatccaaac accaaggatcactcacatct cagactcagc tgtctgttgt aagaaaataa 104220 gtgatgacat gccacaaaaacattgatagt attaccaagg tgtactttaa ttccctctat 104280 ccaaaatttc caaaatgtcgaattttagga aactaacagt gttcaggtgt gaaaatatca 104340 ttgttggaaa taatatatcaagacccattt ctcgatgatt aagcattagt atataggtaa 104400 gaatttttaa gataaatttgttataaagac catctaaaaa tcggagatga taaagtattt 104460 tataagcaaa aactacttctcttaaaagaa aatgttactg cttcttaaac acaggtttta 104520 ctgaatcttt gacctaaactgggattaaat ctattttcat tttggaagcc aattgaaaaa 104580 aaagaataac cttttcaaagttactttaca gtcaaatttt caagcaacat tttccagaat 104640 cacattaggt gaaacatatttatagctaaa actatattcc acactaccct ttgtaatgct 104700 tagctaccaa ttaactattggctatctata ctatgactat attctgaaag aaaaggtact 104760 tagcagagtc ctggctctcaaacattgaca aacttgtgtt aacagcacta aaaaataaga 104820 catacagaaa gaacatacgtagattcccag gtaataaggt ggtggttcaa actttctaac 104880 tataggattt aaaggagaaaatgtaagtat agttcagtag ttgtacaact gaagaggttg 104940 aatttgagga aggcttgaccatatcaaata ggtagataat ttttataaag atagaaggat 105000 gagctaggac tcacattcgatgaactccca tttttttata ataccatttg gaaaatgtct 105060 atctctccta tcagatcttaagtaccttaa agacaaaaat tctcttatat ttctcaaact 105120 tgagtataga gccttttaaattaaaaaagt atataagtaa atcttcctta ataataagat 105180 atacaagatg gttcaatttaatttatagtt ttatggcaga agggcaaatg gcaattattc 105240 actttctaaa gaaattaataagagaccaat taatttgagt aaaaaggaaa tgtctcttgg 105300 attattggaa gtccttaaattttattaagc tagaacatca atttttaaaa tgagcatggt 105360 taaacagata aggggacacaaaaggataaa ttctttatat gacattataa tttaacctta 105420 aatcaagaag catatatgactttcatttaa aagtacattt attttcataa gtatagtgat 105480 agaaactatt cttaaataaagcttcccaaa gcaaatctgt tcttttttca cttggcaaat 105540 tcttttttat cctctaggatcagttcaaat gcaacctctt ctaggaagat ttcaaaagca 105600 tcctaactgg ttgcactacaacactgctcc tctgttcaaa actgcaatgc tcttcatttc 105660 attcagaata aacaccaacttcctgataca tcagcctaag acggccctgc agaaacttat 105720 ctcccattat ctctaaccttacctgctact tctcgccttg acctgctcca gccactccaa 105780 tctcctgttc ttccaacacaccaggtgtgc tccaaactta gggtctttgc actggctgtt 105840 ccctcttcat gaagtctttttccacatatg gctaattccc ttataccttt tcaagtcttt 105900 tctcagatgt ctgttaccttctgaataaag cctaacctaa ccagcccact gaaaatagca 105960 acacagcccc tgccatcacccataacttct gatccccttt tattcagctt tatatttgct 106020 cttcatctat cacttattaccagacctatt taattattta ttatattcat tgcttatttc 106080 ctgcctgctc ctactacaagataacaaact tcacatgggc aggattttat tttgttctct 106140 gattagccta agagctgacacaggttggtg aattaacaaa taaattacat attaacaaaa 106200 ataattaggt ttagtgggtacagggactca cacctgtaat cccagcactt tgggaggctg 106260 aggtgggtgg attacttgaggtcaggagtt cgagaccagc ctggccaaca tggtgaaacc 106320 ccatctctac taacaatacaaaaattagct ggtgtggcgg taggtgcctg taatcccagc 106380 tatgtgggag gctgaggcagaagaacagct tgaaccccgg agacggaggt tgccataagt 106440 tgagatcatg ccactgcactccagcctggg gaacaaagca agactccatc tcaaacaaca 106500 acaaattagg tttaagaattaaaaaaaaaa aaaaaaagga agatttatct cacagattaa 106560 aatattcaaa atatctctaaatagtgcttc attttaactg ccctgctaaa tgaatttaat 106620 tgggaaataa ggggagaacgtattcactta attttctgaa tatagaggat aaatgaaata 106680 aaaattccag aaatcactgttatccatttg aataaagtct gaagtaaaaa aggagcaaaa 106740 tactgaagca tgtcatttgcagcaaatcat tcagaacagc ctttgaaata aagtatatgt 106800 gctcaagtct acaaagccaattagtagaga tcaacaaaag gcccacaact tcttaaacat 106860 tagatgtgac tatgcgcatattcagccctt gggttctcat ccattacttc tttaggtgct 106920 aggataataa gtcaaattcccccataagtc acttcttact tcacacctag ttatttttcg 106980 agaactgatt tacttatccaatcataatac taatgcatat tcaatttaga aaagaacata 107040 aatgaaagaa aaacccataattctattgtc tatagcaatc acttttaaaa tttcgcaaag 107100 gtttacctca aaaacagcattttaacagct atgttgtatt ccttaatgaa ataagaggtt 107160 ttaagtctga cagacctgtgttcaaatttg tcactatgga gactttaagc aagttactcg 107220 ttctaaactt taatttctccagttacatta ttagagaaac atttccattt accacaatat 107280 acctggcttt catattatgctgttctttga caccccacaa tttcacaaat tttacacagt 107340 caattatatt aatatcttctactgctttaa tatgaagttc tcctactcag cccaacagta 107400 caataaacat ctacttacattttcttttac ttttttgtag tttagatttc tcacttaact 107460 ctttaatcca tctacaattataatactcat tatgaggtct ctaaagatta ttttttcttc 107520 ctcaagtaac tatttgttccagcctttcca tttactaaat aattcttttc tattaaattt 107580 tgattacatt attgtatatatggttatata tacatatgta tttttttttt ttctgtgctg 107640 ggccactgac atgactgacagtctatttat atgccaatac caaaatttta atcttacaat 107700 caatgatgtt ttaatatttatttgggtatt cctctcataa gtccacgtaa aaatgttgta 107760 tctttattat ttgttaattttgaaaataaa cagaaagtta caaaattttg ttggaaatgt 107820 aaatttaact ttactaccaaactgacatct ttctatctag aacatggtgc tttcttcctg 107880 ttgttgggcc caaattttcaatgcagatga ttttttaaaa agataaacat aataaagtta 107940 cctcattttc tctcactacatcatttgaac caagttcaca aagaaagaaa aaggtagctg 108000 ccataaaaga gtatctgtaataaccttagt aaatacattt ttgaaggcac tagaaaaata 108060 catgataaaa aaaaccctgcaaataagtac tatagcagaa ataccattac ctccctacaa 108120 aatgtttaga cttttttctccttttgcaaa gatctttgta aaatgaacaa gcacacatga 108180 taaagctgca ataaattacccaagatcaaa attaaccatg gttaaaaaag atgacttgga 108240 aaaaaatgaa aatgactatgaattaacaaa atacaaaggt tagtgttttt tgttattatt 108300 gttttctaac tgttaataacaatataatat gctatataat acctactcca gtgtaggaaa 108360 gctgttccct cttaatcagaaatggaggac cacaaaaaca gtgcttacaa cttctgccaa 108420 ctcatgaaag cagagccctgctggcagcct aatgaaatgc aaggaaaagc atgtagctgt 108480 agattctaaa acctggagaaccaattttta tacagtagaa gaattaagtg aggaggcaca 108540 agaatatgta actcggaaggtatctcagta aaatttgggc cttttctgct gcagaattgg 108600 gggtactcag acaagacgcatcagtatttt atgagaaggt tttcattaat tttacttaat 108660 tcatttttta tcctcttttgactagtttta cttttttttt ttttgagaca gagtctcact 108720 ctgtcgtaca ggctggagtatactggcaca atctctgcag cctccgcctc ctgggttcaa 108780 gcgattctca tgcctcagcctcctgagtag ctgggattac aggtgtgcac caccatgcct 108840 aatttttctt gtatttttagtagagacggg gtttcaccat gttggtcagg ctggtctcga 108900 actcccagcc tcaagtgatctgcctgcctt aacttcccaa agtgctggga ttacaggcgt 108960 gagccaccat ggctggtcttgactagtttt attctgtgat tctaattaaa gaaaacactt 109020 ggaaggaaag ctcccaggttttctgtaaat aaaatgcaaa agtaattata atttataatt 109080 aacaactaca gaaatgattcctaaattaaa atataaaagg gagtaacttc taaataatca 109140 gtaacaggtt tcattttaatctccaccatc tgtattaata aaggctttgg ctttctacaa 109200 atacgattaa taactatcactgtaaaacaa cagtttggaa ctccatgaca ctaaaattga 109260 gtaacttaag agtacatgaaaacaaattcc aaactgattt acccctcata tgtgccatct 109320 ccaattttag atgataattagattttccaa gaaaataatg ctatattcat gactagacat 109380 cagagagtaa tgtctataaaaatgaccctc caagttcatt agttcattac aagtccaaat 109440 agttgtctat atatggtgttggtgatttca gaatttctat cagataaatg tattgtgtgg 109500 cataaagtat ttaataaggcataaaattac ttgaaatgtt gctcatttta gagatccaca 109560 aaagtgtttt aatgaaaaggaaatatgagg gtaaaaaaaa attgctaatc ataattttct 109620 aacagaagtt acgttaaagccaggcatcaa acccttgaga aaatggctat aaaggaagag 109680 gaaagcaacc atggtttagagttatgagag gtttttacta ggacttcaag aatctgacga 109740 ttaaaaaaaa aaagtcttatctgctgcaat taataatgtg ggtataaatg tcaccataca 109800 atacataaca aggagaggaaaaaggctaca gaacactctt acgacgtgta gcaaatttag 109860 agaataacag ctagtatttactgagtgttt tactacatgc caggcactat tctaaatatt 109920 ttacatatat tctcatttaatcctccctaa tcctttgagg tggatacttc cattattccc 109980 aataagcaga tattccttaccagtaaggaa accaaaggat aaaatgtaat ttactagagg 110040 tgaagcccag gtttaaactcaggcagtctg gtgccaaaga ctgtaccctt aactattata 110100 tgctgcctat gcagatcaatattagaaaag aaagactgaa agaaaacatg ccaaagtatg 110160 tacagcagtt aaggagtgagactgattaat ttttgagctg ttctgttttc caaactttct 110220 ctatagagca tacgttcattctaatttttt ataactcaat ctacctcaag gaattcaaaa 110280 aagcagtagg aaaactctaaaatatctaaa gagactagct taaattcaaa gactgacaaa 110340 aataaaccta gagataaagatgcaaggaat ttaaatttat ttaatcataa aaaagaaaca 110400 ctaatgccta agcatattacagtgtatgaa tgtatattat gctatagaga atgacaattg 110460 cgtatttgaa aatggactgaaaaaatgata tgctataaag aaataattca catcagtttt 110520 gatttgaaag ctgtaagataatactacaaa gcaggccatc aactttgttg taagatttgt 110580 ttgtgtaatc tttcccactgaatttttaaa caaaaagaga aacatgtcaa agatagttca 110640 ggttcaattt tgtttcggagggaatcatat aaggaggaat gtttaattca ctatagagcc 110700 acaatggaaa gacctgttattaacacgggt atcaaggaag taatgacaac caaatactca 110760 taattcgagg gccagaattaatctgggaaa ttattcaaca caggttggtt tactcctaca 110820 gtaccatctg gtctctacatcatactgtac cagcaagtag caaccaacca acatagaaac 110880 aggacaaata aatcaccgtaatagtaacta taatgaatga tagtcccaat ttcagttaaa 110940 gtacaaagaa ctgggttgcaatataaaaag ataatcttgt agtcaccttt ttgtctacaa 111000 aaaaaggagg gcaggtattgggaatagaag agtaagggga aatagtcacc tgagcaacat 111060 agcacccatg atagcttctctcttcgcttt aatactataa ctaaaataat cagtatgcac 111120 agcagctact ttccagatttctagatattc aattttggtg tgtagttgca cctcctgttt 111180 gaaacatact atgtttttaaaatttagcag ataccataaa gatgcataat gtctgaaaag 111240 gaaaacccaa atactaaactgaaataaaat acagaaaatg atgattccaa gaagtaagca 111300 aaaaatttca tgaaccaactacattaagag cactaataaa aagggtagat atgataatta 111360 ttaggaatag tatttaatcttcctcctatt ttatttcctg gaaaccagtc tgatgctagt 111420 tcaagtagaa aacacacaatgacataatgt tttcagtttt aaatatttta aaatgtttac 111480 agttgtttta ataacaatttatttttcttt taaataaaca ttttttaagt taggtggttt 111540 tttttaatgt caaacattttaatcactcaa ttttgagtca acaaacattt atagagcacc 111600 tatatgagcc aaatatgggctagagaataa gagggaaaaa gaaaagacat ggtacttacc 111660 ctcatggaga ttgcagtctagcagggaaga aagacatgaa acaaggactt acaacaatgt 111720 taagtgttat caaatagaaggtatagggaa atcttgaaat atatagcaaa agggttctaa 111780 acacgttggg gctgaggggtggatatctgg gagtctggga aaacttctct gaaaaactga 111840 catttaaact aagacctgaaaaatgaacag ccacagaatg ctgatgtgag cgcagcatat 111900 tccaggttga ggaaacagcatgtgcaatag cctgaggctg gaaagagcat agcattcaag 111960 caacatgaag aagtcaagattgacttgcac acagagtaga gaaagggcaa gtgtcaagag 112020 aagagactga gaaggtaggggagcggacta tatagagtgc tttctaagct aggttaggta 112080 ttttggacta aattccagtaataacgggtt gaagttttgg gggagaaaag aatggagtaa 112140 tatacatagt aagatttactttgggataac tcattgcagt tttctcttga ccacaatgag 112200 aatgaattgg aaaggatataagtaaaagca aaagctaact ttgcaaaaaa atcaaagggt 112260 tctgaaaaca aaatttcattttagaaaaaa tttaatcagc ttgacaccaa aattatcaac 112320 actttcccaa ggaattaaatacctgatctc ataagtatct ggcactatat aaaaacttga 112380 aaagaacaca ccatgtttcattgtttctag agttcaaata ctgaggcaaa attcaaacac 112440 ctgctattac caaatcaacaaatggacaga gctggcacat taacacataa agaatttcac 112500 agagaaggca aaaaggtgctatataaatgt gacataaagt taaaagcata agatctgagg 112560 tacatgcata catatacacacaaaaacaga gatataatgt cattggttac tgcttttcta 112620 agcttcagtt tcctcattaataaagtaaga tcagctgagt gtggtggctc acacctgtaa 112680 tcctagcact ttgggagaccgaggtggatc acttgaggtc acgagttcga gaccagcctg 112740 gccaacatgg tgaaaccccgtctctactaa aaatacaaaa attagccggg tgtggtggtg 112800 catgcctgca gtctcagctacttgaggggc tgaggcagga gaatggcttg aacctgggag 112860 gagcaagttg gagtgagccgacattgcgcc actgcacttc agcctgggca acagagcgag 112920 actcaatctc aaaagaataaaattaaatta aaaatgtagg gttatcttaa agagttgcta 112980 tagaaaacag acgagacaaaatgttttgca aattcaaagg tattttatac taacattgat 113040 atggactgtc cctaaacaatcaaatcttca tgtgccataa aagttaattt aactgaacat 113100 agttttcttt tactttttaaaagacttttg ttggagccca attttccccg aggcttcctt 113160 atggagctga acaaattattcctttgttta taaaaatatc tattcagcct gatctgatca 113220 tggacttccc aggtccaaaagatgtctaag aaaacactga atacgtaact ttaaaggatc 113280 cctgaagaaa ttcaaaataaaaagtcatga ccttatgaga aaataatatc ataatttgct 113340 tcacctacac agatatgagtattcaacaaa atcaaaccca ataatcactc tggaaaaata 113400 tgtgatgcaa actaaaagggaaaatggcta gtgattccta attactactg gaattgcttg 113460 ccagatggtt tatatgaagtggaggggata tccctcatca catctataac ctaaaaacaa 113520 atgttatcct attagttacagaagaaatta aaacacagct agctacaaaa gcaacaattt 113580 aaactcacct aagggagtttcatttcttca aagttttgcc cccttttttt tgtcaaccat 113640 taatttcaaa agaaatttaagcagaggaaa aaataaataa atatatattt tgtacatctg 113700 atactttggc ataatgaacattatttccct aaaaaaaaaa aaaatgctaa tacaccttgc 113760 aagtctctca cagctaacctgtttttaaga ggcaaaaaaa agggaggaaa tagaaaggca 113820 ggggaggggc tagggagaaaatagttaata aaacaacaaa acctgtgtca aatagaaata 113880 tgaagatcat tcagggaaaacactaaaaaa caaagaccaa gacaaaaaag aatataactg 113940 agtcaacaat cattaaaccaaaaaaaaaaa agcgaagtat aaaaccttta taagactaaa 114000 attatgacta gaaaaacagaaaatgagctc taaaagtaaa aatggttact gagaaacaat 114060 aggttaaaat aaatatatttaaataagtga tgagtagata tctaactagg aataaagtat 114120 ggattgagta agaaaatggaaagaaaaaac actgaatata gcatattaga aaaagataag 114180 tgaacaggaa aaaaaccccatatattatat cctataattt gctgaattat atgtaactgt 114240 taacttatat attaaaattatgtaatctca tatatttgta atataaaaaa attctaataa 114300 ttatgtaaga aatatatgaggaaaaatata aacctaagag tctaagaaaa aaaaaccttg 114360 attgaataaa tttaagaaattaccagctac agaaaattca aacacaatat tggaaatatg 114420 gcaaaatata gcacaaggtgagaaagaaga gtcttctcta caaagatttg catctagctt 114480 taagtgactg tttgctgtctttattcaaac tagtcttctc agagaatcac aaaattataa 114540 atgtagacaa gatttaagactttttttttt tttaaatgca aaggcttctt agcattaatt 114600 ggatgtctgg gtagtgaagctacttttcaa ggcaaagttt tttccttacc ctcaaacatg 114660 tttaagaatc aggattctcaaaactcctta tcctcacaca aaactgcaga acttaatagc 114720 aaacctccac agacaagtaaaataaaaata tggaaatact taggcaaaac accaaaaacg 114780 atgacaaatg aaagacctagagataaaaag tttactttgc taacatgtca aatgtaagaa 114840 aaatgcaaac aaagcaatcagcagaaattg ctttaattta atgtattaca atctttttca 114900 caagataaac atgcattaaaccaacttcca aatttaatct taaaaacccc tttaatgtat 114960 ttaggtctct tctttcctatctccccttac tcatgcacat ttattactga agtataagca 115020 aatatagaat aaactatatctgaaaacagg cataatgtgg gtatggaggt aagagaaagg 115080 acaatactaa agattcgctaatacctttgg aagtaaatgc tgctatgcca agtacacact 115140 cacatctctc ttccacaataaaagaatcac aagctagtaa taacaacaga tcagtgggat 115200 cttttgtctt tgcttttgaaaacagtatta aaggaggttc tagagcactg gaaggcaggt 115260 gaaccacttt gggtctcttgctgagactga gttctagttc aattttcaca acttacatca 115320 aagaccaaaa ggttcaaagtagttgggaat tctaagcaca taataaaata aaacaggata 115380 agaaaacact gagacaagctcaagtggctt ctcaaattgt ataggtatgt attttatatt 115440 ccaagtgtaa tgaactgataactcagtcta ctcataaacc ttaatttctt aaaaatcagt 115500 ttctggtttg gtgattttatcttctcttac cacaaagcta ttcttggatc aagcttctct 115560 tctttctacc aaccttcattccatttttgt aataccttac ccacctttga actttacttg 115620 tcccatccca gtgtatgaatttcatcaact acctactact tttcatttaa tatttactaa 115680 tgctgaagag ttgggtctctaaagagcaat aaaacataat gtctgtcctc caggacctaa 115740 cagtatagta gaggaaacaaaggtaaataa atagccataa ccatgtgata aaatcaatag 115800 tagagataag taaaaccacttaattctgcc cagtttaaca tctgagtttt aaaggataaa 115860 cagatatttg tacaacgtacagaaaacaga ggggcattcc agggagaaat aaaacatgtg 115920 aggagacaaa aggatgaaaaccaacatggc tgattctaag aactgccaaa gagttgtact 115980 aagctagagc acaaagtgcaggtgaggaca tggcaggaaa agtgggaaaa ggtcagtctt 116040 gtgtgacaca ttaaaatggttgacactatc attcagtcac tctcaatggg ggaaaggagg 116100 aggcatgaca tggtaatatgtgcacttcaa aaagtttaga gcagtgataa ttttgcccag 116160 gagatatttg gcaatgtctggagacttttt aaattgtgac aagggggtag tggggatgct 116220 actggcaatt agcaagcagaggccagggat gctaataaac atccaacaat gcacaggaaa 116280 gctgcctaca tccaggaattatctggccca aaatgtctca acagtgccaa ggttaaaaaa 116340 ccctggttag aatctgactcctaggataca tacaggaata gactaggggc aggggctcaa 116400 gtagcaatta agttctgggagagcagaggt cttgttcttg cttatccgca actccagacc 116460 ctagcccagt gccagatataattagagata tacaatattt actcagcgag tgaatgaata 116520 atgtagaact ccaagcaagaagtaccaagg cctgaaatgt ggctgtggca atgataatgg 116580 agaacaaatt caagaaagtagaataaacag gtattattta ttaaacggac ataagaaatg 116640 aacagtaaat ctaaaataaaattatctcca ggcttctggc ttggagtaac aaggttcaga 116700 gagtgtcaaa aattacattttaggtatttt taagtttgag atgaatgtga gatattcaag 116760 aggtccaaca gtttccatatggtttgaaat atctaagaaa atccaatttt gccacaagct 116820 taacctaaaa ttatcctctgaactacagta aggagtccaa taaaaaatta acaaacccta 116880 tgtcaagtac ggtatcctggactggatcct ggaataagaa aacgtaatta gtgggaaaac 116940 ttagtgagac atgaataaggtctgctgttt agttaacagt aatgcaccaa tattggctta 117000 gtagttctga gaaatagaccaggtaatgca aaagtataac atttggggaa actgcatgag 117060 gggtatacag gagctctttaaaccatctgt gtaacttctc agtaaataat ttcttactcc 117120 aaaattaaaa gtttatttaaagaaaaacta ctaccccaaa tgtgtcaaaa ttttaatatt 117180 tgggatctat attaaacgtttaaatctacg tacgtatctt aagaaaagct aaaatatcaa 117240 gaattttttc ttacctccactgatacttgg taataccaca ctgaccaagg aaagagcaaa 117300 gaaaactttt aaaggtagccagacagaaaa tggcaaagac tcaacaaaag aagaaataag 117360 tcagtactac aaacattcatatatattttt ttcaatcttc tgaaccatac tgtaacagct 117420 tgaaataatg cattgtaccactatgcaggc aactattctg gcaagaagac tgatgaatta 117480 tttctcccca acaccatcctgttcattact ttatagcgat aataaaacaa aatatatacc 117540 atggtgaact ctagcaaaacacagacacta acctatgact atgcaagttg agtcattttg 117600 gtcagtctag cttctctgcagtgctttcaa aaaatatatg taaatacaat ttttaaaagt 117660 aggcaaaatg ggcaatccactacaggtgtt tcttaaaata aagcaaagat tttcctgaaa 117720 atcacaatgg aagagagagagaaaaaaatt atcttaaact ctaaaaataa aatagtcttt 117780 cagaaaggta catcaatcacctgcttggca attaattctg ttacctaaat gaatcaatta 117840 catttctatg cttggatgcaaaacccaagg tatttttgcc atacgtatat atagggttct 117900 gtaccatctg ttgtctccgacatccactac ggatctcaga atgtatctcc tgtgaataag 117960 ggaagataaa tgttcctctctccttgtcag cagtatttac taatctgacc atcaacgacg 118020 tggcctaaaa tattatatttgattttataa atatttggtt cccttttaca aaaaatgact 118080 aacaccaatt ttcttgagtagccaagtgtt attattaata aattcagttt actgggaata 118140 aagcatagca taatggagtcaaacagtctg ggttgaatcc tggcttcact tctcactgca 118200 tgtgtgaact tggtcaagttaccaaaatct ttccatgctt cagtctcctc tgtaaaataa 118260 gcataatagt tcctacctatagaacattta aggttttaaa agagtaaata aatagaaaat 118320 gcttagaaca gtgtctggcatacaggaatt actcacaaag caaatgttat ttaccatcaa 118380 tcattcttac actttcattacctaccacag gcctgactga caatgtactg aaagaacaag 118440 cataacgtgt tctccttattatgtggatct atagtttttc aaagacagga taaacttttc 118500 ctaaatggga aaactcctataatattttat ctttcccttc ttgcaggaat cctattatac 118560 caccttagaa tacttttctaagtacaaata taccctcgtc tctcaaattt ttttgttgtt 118620 ttaatggttg tttattatagcaagattata tattgaaatt atttaaacag gacaatctta 118680 tgttttaaaa aaaatcatagatgattaccc accacgcaga tatcacatac gttatctctg 118740 aaaagtaagt cagagcaaacaattcagaat acatcagaga gtcaaaaaca tgtaaaacat 118800 agaagaaagg ataacgaagcagataaagtg tttaagtccc ataggaaagg agagagaaag 118860 gaacacagag gttattttaagataatgact gagaattttt caatgtcaat aaaagacatt 118920 tccagaatct aagcaagacaaatttttaaa aaattaacat caagacatat catactcaaa 118980 ctgcagaaaa ccagaaagagaaaaaatctt aaaaacaatt agagaaaaag ggattgcctt 119040 caaagtagca agttagatagtagatttaaa cccaagtaca tcaatgatta tatgtaaatg 119100 actaaatgtt ccagataaaacacagattat catattgtat ttttaaaagc cacttttata 119160 tttttaaaag acaagaaataaaaggaaaca aaaagttgaa agcaaaatta tatatatata 119220 tatatatata tatatatatataaaaatgcc aaacaaaagt catataaact tacgatctgt 119280 ataataagta tccagaaaaggaagaattaa gtaagatttg aacaggtgga agaaagaaga 119340 gtaacattcc tggctaggcaggaacatgag agtggaaaag aagctatgat tgaactttga 119400 aggtctctga aaattaggagtacacttaga gaaagtacaa cactattaaa atatcttaac 119460 ctctttatac tatcttcagcagaagagtga cacaacaaag gtagaactga ataaggttac 119520 tattacagtg ttacacactatactgggagg gagagagaga tagaagacac cataggcaag 119580 aagattagtt tggatgatgctgtattaatc cgggtaaggc aagggcctgg tagtagcaga 119640 tgtgaaaggc atgaacctaggaggcatctc aagaagacat acttgcatca gtactccctc 119700 tttgaaactt tagccaaaaaaagaaaaaaa aaaaaaagta ctgtgctctt aaaaagataa 119760 ctacttttgt ctcctaccattataactaat ctgaattata tattgattct actaactcga 119820 cctaataata tataccttaatatggaactt tcgtaaaaat aaaattccaa tgagctaatt 119880 ggcctacata aggtgcaatgtgcacaatcc ctcattatac atgacttttt cactattaaa 119940 actactacta agaaaaaaaatctatttttt tctttttgaa tgcagatgta cataatatga 120000 agttctctaa taccacagtaactaaaaaac cttttcattt tcaaaagctc tttaccaaga 120060 ggctattaac tactagtgaactcaaacaac tcaccaatgc tgggtgggct accatagtta 120120 actggtgact caggtggtcttccacagtgc aacgcagcca gagcagatcc tttccacaca 120180 acatgcttgc agcctattaaacacatgtat ttttatgcat acaaagaaca caaaaacaaa 120240 agtgagataa ataatgtctaaatcctatga gaaaattttc atacttttat ttgtgcgtag 120300 taaagactgt cttccagctcctaataaagt ttgtactcca ggaacacttt gaggaatttc 120360 ttgttcaaga agaggtcctagtcgatgaca tatttgcagc aagtgatcag gtgctaagtg 120420 tctgtaatac ttcacctattatgtaaaaga caaatatagt aggtttcagt ttatcatttt 120480 aattttcaaa atctttgagcaacaataaaa aaattcatcc aagtataaaa tattttgttt 120540 tgcgtctttg atgtaaagtaaatctccaga ataattaaga attaagaact gatagtttgt 120600 tattaaaaaa tttaagaacacttaacatct atgctgaatt tcataattta ccaaaaacct 120660 tacagagaga aaggcaaaattccaactgct gctttaaata tctttcaatc ataaaataaa 120720 gctacccact ataaaaagtttgagcacttt tggaacaact tcaaaatact gcttaattta 120780 taccggcatt tgaaaccatgacatgaaatg ctaatatttt tattagtctt tcagtaaata 120840 aacaatattc actatctaaataaaattata ttggaaaaaa atactattgt attacttcat 120900 aattagctat caagttagaaaaaaatttcc acagtagtat ctagttcagc tattctcaaa 120960 gtatgttttg ggaacccctggaggtccctc agataaaact tatgaataac actatattag 121020 ttgtttttca ctttttctcatgaatgcacg gtggaggttt ccacaggaca cataacatgt 121080 gatgtcttaa cagactgaatgcagaagcag ataggaaaat gtctcctcta ttaagccaga 121140 tattaaagat tcacagaaatgtaaaacaat gccacgcttc tcacaaattt gttttgtttg 121200 ggaataatta ttataaaaatgttacttata ttaaaataag attagtttat tagtattatt 121260 taataggtct ccaatatgttaaatgctaag tttctaatat ggtaaatacc aatagattat 121320 aagctacaca aataaaggaacttcaataca ttttagtaag tgtaaagggg tcctaagacc 121380 aagaaatttg aaaattgttcctcaagttta ccaagtaatg gcaactttaa catgaattcc 121440 ttttgataag actgatgtggggggaggtga ggatttaaat catctcattc catcttgcaa 121500 tatctgctat actcttaactgcagaaatcc atgaatgata tgtttttaaa ggtagctaat 121560 acccatctaa actgaagccaataggagaaa cctaccttac tctttatcaa aatacactcc 121620 ttctttcaca aagataacatggagccatac tgccaccaaa taatctttgg taagattatt 121680 taaaacagca gtttggcatacagtaggtga taagccagta aaatgagtat ttttggaaaa 121740 aggagttcta atacagtttgtatcatatga attatacata ttacctcctt gttttgcagt 121800 caaaaagcac actgacattgaagtctctga aaaatcctga gattatttcc caaactcatt 121860 tagctacaga atcccttttttccctaataa tatctatcat attcactcag aacatacttt 121920 aggaaacact agtatgattagctaaattaa aaagcattta aaagaaaact taccaaaatg 121980 agtttttaaa atcgtatacttttctttaat cttccccaaa ataatttact caaaaataaa 122040 atttagaagt ctagaatacttgtaaggttg cttccagttc taagcttgca aatgattatt 122100 ttaatgtgac ttaattgatcaaaattcctt ttaaaaattt tactttaaag aagatggaag 122160 ttcattactt attaacttcagatgtgtgat gatcctgttt tagtatcctc tggcaaaata 122220 tattttcagg tagtgaaactgaaaatcctt actgtaatat tctatctttc aataaaatat 122280 tatgaatcca ctctgactcaagctttcttt ggtgatttag aatgtttgaa tttttcaaaa 122340 tcaactttca ttttaaagttagaagagata cttccagttc ttaaattcct tgtgctttct 122400 ctggcttttg agactttatacaagctgatg cctctgctgg caatcttgtc ttacctgctc 122460 acctctacac ctcattctccttcatgtctc agtctatgtc tcactcactg ccttccatga 122520 cctatttaca ccacctgtgcccctttttgg acactttgtg ttcccacagc acattatact 122580 cctcgaatgt cccttcatccctctagcact gtgtagtact taccatatta attgttctta 122640 atatattttg atacttagacttttaagaat ctaatgacag ctacgatctt cttccctgca 122700 aaaatacaca agccctaccattatgtgccc tgttttgggg gttcataaga ctcatgcact 122760 atactaaaat tgccagtttacttgtctgtg tcctgcataa ggagagattg ggccatgttt 122820 acctctgtct acccaatacctaatgcagta cttatagtta agtgcttaat aaagttctag 122880 ttggatatat gaagatttaagaatatgcag aaacgactga cttccccact ctcaaaaaac 122940 ccaaaacatt ttgttagcacctatcccagc acataaaaat agatgcagta aaattttttt 123000 acatggtata attctttattctaatagttt tggggtgagt ttgtttgttt tgagacggag 123060 tctccctctg tcacccaggacggagtacaa tggcgggatc tcggctcact gcaacctccg 123120 cctcccaggt tcaagtgattctcctgcctc gcctcccgag tagctggaat tacaggcgcc 123180 ccaccaccta acctggctaatttttgtatt tttagtagag acggggtttt gccatgttga 123240 ccaggctggt ctcgaacttctgacctcaag taattcgccc cctaggcctc ccaagtgctg 123300 ggattacagg catgagccacagcgtccggc caattctaac agttttaaaa cactttttaa 123360 agaaagcctt agaacatgtcttcaaacaaa ttttagacaa aacagattaa agtaaaggta 123420 ctcagaaagt atcttacttaagtggcatca gggaacacat atctcaatgc ttgactctct 123480 acttgcttcc tcttagcagtccctgaggta ccaccatgaa agggtctctg gaaagaacag 123540 tggaaacaga ctaacaaacaatgctattat cctctctttc ccaagaatcc tcttccccac 123600 ccctcatttt ctcagcagatgacctaacct actttacagg agaacctttt ttaaagctga 123660 agctttgttt cttccctatcaaatctgtaa acctatctac acctgtacca attctgtctc 123720 ttattaacac aactgtccctcttaataaat atttaagatc caatccctct acttatgctt 123780 tgaatcctaa cttctctgactgcacggaaa tcctacacta taaattagac ctccacattc 123840 tagtatgtac actaacttcctctcaaccaa ctccttccca tctacatgta aacatgctca 123900 ttttgcatcc actttaggaaaaaacaaaaa tcctgcctaa ctgctattat ccaacacctc 123960 cccacccaaa tatcctggctacccctttcc cgttctcttc ctctccggaa acatgttttt 124020 aaaagaatgg tccatagtccatctaatttc gtatcccatc ctctcctcaa tctactccac 124080 actagctccc acactcatgactttacaaaa aatagctctt atcaaaagtt caccttcaat 124140 tatcaataac tccaataagcatttttaaat ctatacctta tttaatgtcc cataatattt 124200 cacctaactg ttgaacacttcctcatttgc aaactatctt ctcttaactt ttgtgacact 124260 ccttggcttg ctttcttcctctccaaccat tccttctcat ttttctttta ggcttatact 124320 cctctatata gccattaaatagtgaagttc cttaagatcc taggtaccag agtccagttc 124380 cagatcctct tttcttctcactatatactc tctctttgga caattgttat aacaatgatt 124440 gccaaatttc tatttatagcatagacttgc atagcaaact ttcttaaaac agctctctag 124500 agccccaaag catctgaaactcaacatatg caaaactgaa ttgatggatc ctcatgaaaa 124560 cattccccac taaagtgttccctacctggg tggatgtcaa ccccatttat ccaaccttgg 124620 aagccagaaa ccaaggagctgcattttgca cacagttcat tccttcctcc ttcccatcat 124680 attcccaata tccaagcagtcaccaagttc aacttaattt ttccttccta tttttaaatc 124740 catctacctg tatctccataacagtccaaa taatctttgc aataaatgca tacctttccc 124800 atatgcactc atgccccattcaaatctatt ctctatactg caattagaat gttctttcca 124860 aaatacatat tggatcaagtcacccctact taaaacactt ctgatgcttt cctcactctt 124920 tggataaaga tccaaatccttaacttggtc tatcagccca gaaatgcatg tatggtcact 124980 tcttattttt ctagcttcacctggcacatt cccagtccct ttccccaact ctcacttttc 125040 acgtttcaaa cacatggccttctttcaggt tatttacgca taatctctct ctcctgtcag 125100 actttatcat atagcatacactctgcattt ccccacactt ccttgcccag acaactcttc 125160 catgtgtctc agatcttccctctaatgtaa cttcctttgt ttttctatac tctacacaat 125220 ccaagtctgt tttcttggttgcacacttcc tgtgactttc ctttattaac tcaatatatt 125280 ggcttgtgat tatacatttaaaagtgtaat ttaatgtttt tctacttcac cattaactac 125340 aaaagagcag gggccatgaatctttttgct cttaactata ccacacacac acacacacac 125400 acacacacac acacacacacacagaataaa caaaaatatt ttttaaaata aaacaatctt 125460 ttctactttt tctaaacattctttataaac atattaatca tattcatatt cttcataaat 125520 attaatccat tatttacagatatacatatg tgattttcag ttttcaactt agtaagaacc 125580 ccatatcttt aatataaacttaagctttta atttaaatta gcttttattt cactggtaaa 125640 taattaaaag acacatttaaaataatataa taataaaatc tcttactata ttgtatatat 125700 gtggtttctc agtaatctgccatacaatat tatttcaggg gaaaaataac ccctcaagat 125760 ccccaatttc tgatatacgagttactttct gtgaccctaa gtgctttcaa attcttaaca 125820 ttcaagacat aaaaagtatgaccagattat aaagtcagtg tgataaatta tactaatata 125880 gctaacacat attggctgcacactgaatgc caggccctat ggtaagtgtg gtaagtttta 125940 catggaacta ctcataactctgagaggtat atactatcat tattcccatt ctataaaaaa 126000 attatagaat ttatttaaaaagatattgag accttcccaa gttcaaacac agcacataag 126060 agagtcaaac catagcaatctaactctgga ccctacaatt catactatca cacaaatgac 126120 ctattacctc aaatatgtgtatatatcaat gtgcaagata taagcaagtc atacaacaga 126180 cattttgaat agttttcaacagacattaaa ctgagccaga aaaagagaaa catttcacag 126240 ttcacttgca ctactaaggaaactagcata aaagcataaa ttcctatagg taaaagggaa 126300 cactttaaaa aattctaagggtaaaagtag aagataaaac tacaatattt ataagattat 126360 actgctctaa acccttaatttaaaattaga aagtaaaaac agattaaaga gttaatacca 126420 aatttgttac tattttttaaatttccccaa gaatgcccat gtatcagtag tgctcaaaac 126480 tttttaaact catccaccctggttttgttt ttgtttgttt tttaaggggg cagggggatc 126540 tcgttctgtt accaaggctagggggcacag tcacagctca ttgcagcctc aaattcctgg 126600 gctcaaacga tcctccgacctcagcctcca gagcagctga gactataggt gcgttacatc 126660 acacctaatt tttattttatttttttagat acagcatctc tctatgctgc ccaggctagt 126720 ctggaactcc tggcctcaagtgatcctcct gcctcagcct ctcaagtagc taggattaca 126780 tgtatgagcc accatgcctagctctcatcc ctttttgatg aacaaaacat tttctctcct 126840 ccaataagat gcaagaatgggccctatgga tgcaaatcct gatgccatcc cattgagatt 126900 cacacctcta ctggctaaaccaggaggcta gtcagagctt tttcaaactt atgtcccttc 126960 cacctccgtt ctcagttgagttgcttgcta tgggaacaac aatctttggc taactgtcca 127020 tccattttaa ctctttttcatagttaaaat ttgaattagc caaaggtatc ctttttttaa 127080 aatatcatgt tatattatttagagtgcaag tcagcaaaca tttgtaacca tcatatggta 127140 aatatttgag gctttaagaataatatacta tctccattgc atgttcttat tttttaaaaa 127200 caattcttta aaaatgcaataacaatgctt agcttaatgg ccttccaaaa acagatctcc 127260 tgcacaattt acccacagcagccattagtt taccaccccc tgatcgaaag aatgattcat 127320 ggttctagca acgtttccatcagcaagaac aaaagaattc tgtgaaacag cagcaactct 127380 gctcattcct tgtccatcttggcccaagtc ataaatctgt atcatccctt ttccagatca 127440 catatataaa gtatttctaaaattatccat tgcaatttga acaaaagggt catcttctga 127500 gaatgtgaat tacagtatggaagaaacaag aaactgagct ctttgagagg tttattatcc 127560 cgcatttttg gctaaaacaacattttctga tagtatgcta cttcacataa acagccatcc 127620 ttcccagcca aaaaattttgccattatctc agtggaaggt attgttaaaa ggcaagtgtt 127680 atcagtagga agaaaatacaatggatctgg aagctgctgc attctaccag acttacagtc 127740 actaagaact ctactcagtttttaaagaaa tggtcagtag tttaaaatgc gaaatctcac 127800 tgggcatggt agctcatgcctgtaatccca gcactttggg aggctgaggc tgatggatca 127860 cttgaggtca ggagttcaagaccagccctg ccagcatggt gaaaccccgt ctctaccaaa 127920 aatacaaaaa ttagccggacgtggtggcac gtgcctgtag tcccagatac tcaggaggct 127980 gaagcaggag aattgcctgaaccctggaga cagaggttgc agtgagccaa gatcatgcca 128040 ctgcacacca gcctgagtgacagggcaaga ctttgtctca aaaacaaagc gaaataaaca 128100 aaaaacccca cgaaatctcaagtcacacag cctgggttta aagttgctaa ggctgagggt 128160 gggaaaaaca tttactctttctaagcctca gtgtcctcat ctgtatgact ggtatcacaa 128220 cagtcaccac cttggaaagtagtcataaat tattaaatta aaccatatga agcagttagt 128280 actgtaccta acagttggctgttactttaa ttacattcta tattacatat tgacccttcg 128340 tgttgaacaa aatctttgtaaatctaaata ggaaaaaaat ttgagcatgt ttttaacaac 128400 cttttcaaag tgatgttagatcaatatatt cattccaatt atttgattta gctgtgaaga 128460 cctagaagtg cccttctttcctctagtata taattattat gaaaataaga ccctgctgtt 128520 tggcaccagt atcatttgtctaactaggct ttcacttcat ccttatgttc tgaacaccta 128580 attggttcta aaaaagtcagtttttcagat cttctcaaat ctattctctc acagttttgt 128640 cagatataaa aggctagttacacttctgct ctctattatg tttttgagtt ctaaaaggcc 128700 agtttattgg aatatagttcttatttgtac actactgtag catataaaca aaattataga 128760 aatacaatat attgtatatacattaattat attttattat ttataatata taatatacaa 128820 tatataaata taaatttatagaaatactat gtgataatta ctgtgtaagg cctatattaa 128880 aatcccagcc cctaaaattctaaaaacatc caagcttaca attataaatc tgttactaac 128940 agtgtgggtt aaattatatctataatcttt aaagaaagaa tgcattttct gattttttaa 129000 ctgtaatagc ttctccacagaaaaacagag tacttacttt gtgctgagtg ttcccaaaat 129060 ttatttatct tcataagcacataagcttaa ctactctccc tatttcatac ataaagaaaa 129120 ctgaagttca aaggcagcagtttgtctgag ggcacacatt tggaaaatag gagaaatagt 129180 aatcaaaccc aggtctcctgattccaagtt tactgatatt tttattatgt tacagcttcc 129240 ttattagaac tttagtttttctccccatcg acacgtagat ttgattaaaa acttaataga 129300 acccatataa gtcagtacaagtcaagtcct ctaacctggg taactattct cagaaggacc 129360 cttagatgcc tattatttctttataattat aataaaatta atatagaacc ttattaagtg 129420 taaaaatctt gatggtctatttgctcaagt aattgtgaat aaacaagctt caaagaatat 129480 gtcatattca gaatttacttaactgttaag aattcattta gataataatt cagtttacat 129540 tatcaataca aataccaacacaaatttgtc atttaaagaa aatgcaatac tataagaaaa 129600 acaaacaaaa aaagaaaatgcaatactacg cttccaaatt ttattcatca taaaccaatt 129660 acatcttgct aaaaaaaagagactctattc agaattgagg tttccataaa ccaaagtagg 129720 gatgctccat aaaaaataatttaaaataca acaaaatgac aacatttaac tgcttaaaat 129780 aacaaatttt caagttttgatgtttaagtc gtcatatgtg ctaatttgtg taattttaaa 129840 attctcttta aagcattattagtaaaacgt taaactcaaa tctaggaatc tgatgaaaag 129900 ttactgtgta ttaatttaaggacgaaacat cctttaactg cttatactaa ggccaatgta 129960 aataatcttg aatgaccagtttcattttta atgtttcagt ttcaagcaca gtactcaaaa 130020 taacacaatt cttatacaatgacagcaaag ttgtttcaga caacggatgt ttcactaagt 130080 tgcctagaat ttagtgtctctacacccaaa aactaaacca gagtcaaaca caaggtatgt 130140 atttcttgca ttatactataacctttccca agacaagtta catgcctttt tctattcatg 130200 acagagacca aatagaccatgacacatgac catgggtcag ctggagtcca gaacacagtc 130260 atcctccaat cttcatgggggaatggttcc aggaaacccc acaccaaaat caaaatccag 130320 gatgctctaa ttcctcatataaactggcac agtattttcg tataaccttt acactcctcc 130380 tgcacacttt aaatcatctctagattactt ataatatcta atacaacgta aatgttatgt 130440 aaataattgt tacaatgtattttaaaaatt ttttatgtat ttttttctaa actattttga 130500 tctacagttg aattcacagatgtgacaccc gcagataagg aaggcctgct gtacatgaat 130560 tcttcctgtg tctcttctgcaaaaaaacct gccatagcca tctgtactgt catggataac 130620 ctagggctta cctataccacacatctcatt ctccttacaa tttagtttta atataagaag 130680 aagctgcatt cgactatgttgccacctaaa ttttcttatc aaaaactcct catccaacca 130740 tccttttctt acctgtgatgcctaagctca aatacggctg tttttgagtg tgtaaggtaa 130800 ataaaggagg acctgcctcacaactgatga ttgccttctc tgtagtaact tgtcaactta 130860 cattcatcac tattcaataagataacagtt tgtgattttt cagtaccctg ctttatcaaa 130920 ttccatcaag aaaaaacatgttatcatttt caccaatttg ttataaaata cttacactcc 130980 tctatattcc ataggtccaataacattatt cactgcaaag taatttatta actcacaatt 131040 tcctcataat ttcattgacatagcttctca aaaaataata gaaactgaga atgttcacat 131100 ttaaaatgtc tttctaaaattttaaatttg attcctataa tagcctttgc cacttttaga 131160 tataaccaca aaagcaacttaaatatccta aaattagctg ttaaaaattt ttttctaagt 131220 aaaagtgcat taaaataggaagttatttta aataagtatg tttggtattc tctggcaact 131280 aaaggctact tagcttagtattacagatat ttttctatga attctgaaat ttatacaagg 131340 aaactactag taagaatgaaactaacctat ttagtattac ttgttcagag taagttgtac 131400 aagatacatt ttatttgttacaattctgta gtgacatggt aaatacccac aaaacttgag 131460 aaagggaaga atgactgtcaattggtttta acttaagctg aagctgcatt agactattat 131520 tattattatt ttcttattattcatccacaa ctttccagat tatgaaaaaa aaaaagaaaa 131580 ccaaaaacta acttacaaagaaattctgaa tcaactaaaa aactgaaatc ggttaggatt 131640 tattttacct aaagctaaagtctttcttga attctgttta aaatatatat aaacagattg 131700 acaaaacaga agtcaagacatctcttctct gacagtttcc aaaaagaata caaactattg 131760 tgatggttgt aaatctcacaaataactgta tagaaggagg cagacgccat agccaaattc 131820 tcttcatata ttcctaaatgtcatttgatg attacccaaa gaaaaaaagc tttgcatatt 131880 ctctaatcca ttcaggatatgtcaaccacc caaattattt cttaatgttc agtgttccat 131940 aaaaacaagt cacagtagaaatcagtagca caatttttcc agaggtctat ccacaatgcc 132000 ttaaccatga tttatttttggtattaaaca tttttccttt attttttaga cctgtttcat 132060 ccttgagtct ataaagtaattatagtatct tccgaagatt ttttttttct tttcttgaga 132120 cagggtatca ctgtgtcacccacgctggag ggcagtggca tggggcacag cttattgcag 132180 cttcaacctc cctgggctcaggcgatcctc tcacctcagc cttcggggta attgggacta 132240 caggcatgcg ccactacacctggctaattt ttttttttag tttttgtaga gatggggttt 132300 tccattttgt ccaggctggtctccaactca tggcctccca aagtactggg attacaggca 132360 tgagccacca cacctggactcttctgaagt tttaatgtgg cctttttata ctgcagattc 132420 tatgttcaga aagtatatacatacttgtgc ctggaataaa aatgtaaatg cttttcttaa 132480 agaaaacttt attataaagctctaagcaga acaaccttta ctaccactac taaagttctg 132540 ataatagcaa accaaaacccttacatagta cttgattcat gccagttatt actcacagac 132600 cacacaaagt agaagctattattagcccat tttacagaat ggaaaacaga ctccctcaat 132660 acgattctgc ctcacaacaatcaaataaaa accattatgg tttgggaaag ggacattcca 132720 gctcccgctt tatgctcatgccgctttaca actatttaag aatattaaca atatagtaag 132780 tattgcattt aaaaagtttgtaaatgcctc aaattttaaa aaatggtata agcatcaata 132840 gaataattct atatgtaagaaagaatgaag aatgctcctt cagcctctca gcaacatatt 132900 cacacctaac attttattcatcatataacc cttcacgcct aacatatttt attcatcatt 132960 ataacgacca tatgagattaaagctgtttt agagactacc acgcaaagct tctatttcat 133020 tgatactcta ctaaaaaaggaaatagtaac tctactacaa ctacacacat ttactttatt 133080 acatgttcac ccaaccccaaaaaattataa taatcaagtg ttgaaactat gttatcttca 133140 atatagaatg ggaatccctacttctaaaac atttaatatg atatcttttt tttttccctg 133200 aaagttgtct ctaggttttataccttaact ttcacattaa tcagcacaca ctaaataaat 133260 gtatacctaa gatatatacttaaataaatc ctatccatca ttcctattca tctctgaatt 133320 tgagaccaac aataatgaaaactagtactt aaactatgat ggaaatcatg gtaattttgg 133380 ggcattttac aacgtagttagtgtctcaaa tcatctttgc aacaagaaat gatattacca 133440 ccaaagaatg gcactatgaaaagcatttat ataattttgt aacctatgtg atttctactt 133500 ttctgtgttt tggaaaactaagctctaaga atgaaataaa gcttagttct taaatacaat 133560 gtactgctat ttctagttcaaaatcacaga ttttcagatt gaaaaaattt caatccactt 133620 atttttcaaa tgagataactgggacaaaga gaaattccat gacttgccca agattaccta 133680 cagtttaact gtcagcggggcttaaaacca caatccacat ctcctgactc ccaatccttt 133740 cacttaaaac aaacaagcaaacaaacaaaa aagatttcta ataaagtgga ataattttaa 133800 gaaaggcaag tatcactattttacaaggaa aaaattaaat cattttaaca gattggcaaa 133860 acatgaacta gttcttggggggaaaaaaga gaagtcttac aagaaaaaat gtaatcaaga 133920 gagtgccaaa ttcggtaaaatgcttgaaaa ttctgcctct agatctcgta aatatgcaat 133980 catcattaag tgacaactagaaagcagact taataaacta actagattca ctattcaaac 134040 taagaaataa acaaatgacaaagctttcct ttcgtccaaa aaaagttttt tattctacag 134100 tttaagaatt ctgatacttggaaaaagtgc cccttttctt taaaataaat ctcatatttt 134160 aaaaaatgta aaatctaattaaacgtatac catagtacca aaaacaactt ttagcttcct 134220 atccaattcc atttactttgttaaaaatgt tttaaatctt aaggtagatg gtgataatca 134280 gtcatgtttt ataccagagacagaaacaac cataagatac gaccatttcc tttctcaatc 134340 acacttgaaa tgaacgcatcaattttaacc tgcaaacttt taaaactgct cttaaaattc 134400 tactttcctc ttgattaaaattcaaccatt gcgattgtaa ctagactaac tacagatgat 134460 cagtgactat ttttaaattcacatctacaa atattacacc ccattttaag cagcaataat 134520 ttgaggtttc ctagaaatttcaatgcgatg tgatatatga gttctcccat ttaaaatatt 134580 gctcagttta ttagttaatacaacaaatca tttccaggta gagtagaaac taatgactca 134640 acaagtaatt ttcaaatcaatgttaaataa attcaactcg atatacaaca acgtaaaact 134700 ttttaagtca gaataattaaaatagaaaat actgtacaag agactttgca tgtgctgact 134760 tagatattaa acagcgagatcaactattga acaaaaaaat ccagtgttcc aaatgttttt 134820 agacctaact aaatctcaactaaaaaggta aaataaagtt aactcacaca cctagatata 134880 cagtttgatg gatgagaaagcacctcaaat ggtaccttgc atccagtaga tatagagtaa 134940 gcaatatgct gaatgaatgaaaagagaaaa cgagtcaaag aactccaagt tctaataaga 135000 tttctaaact gtctgatgagtatgccaacg ttcctgttct agtaaggaga aaactccaag 135060 caagaaaaac cacttccattcaaaataggt gaattttgag cataatacat agatagaaag 135120 aatgcttact gtatcttaaatctgcgatgc agactaggga tagaaattca ctttactaat 135180 aattcctccc cccaccctccccccaaaaat taaattaact caaaatcaaa attgatagct 135240 catttttact gaaaaaaaaaacaaaaaaac aaaatgatat tcctacgagg attagccatt 135300 accataattt agccagataacattaagctg cttcatttaa aaaatgtaac attaccaaaa 135360 gattaagaaa atgcagcattcctcagtgac ttaaggtttg tgggttttta agagatgcac 135420 agatgtaaaa gcagatgcaaagacgagttt tgtaaaacct gccccatctt aaaaatggag 135480 tattataatc tttgcgataattttttcaaa tatcaaggaa gacatgtaaa ttcactgaag 135540 acttctatca agtatttgtaaacctaaaaa ttaatttcaa attagtaaat cttggagttt 135600 acttccagct ccattcactttggccaagaa ttgaatgaaa gtaacccaaa tcactccttg 135660 aaaattaaca cacgttcagtgtgaaaatga atacactaat acactgttaa atctccatta 135720 gatgtattaa acctcagtacccttgcttat ttcaacagcc ttgagcggtt atcaacatct 135780 tatattaaac cacaagagatttatacacaa aagttaggaa atacactaca taccaaaaaa 135840 agcgccatta taatcatgtcctgctttcac ctcacaaaag acactcattc taagctcgct 135900 gaaacttcct agtcattagagaagttctga tgaagtaaca ttagtaatca taactatctc 135960 aaaacagtta caaaagcctcataaaatcaa cacactacat aaatttcaaa ggcttggtgg 136020 gtccggtgcg actgctttaactgccccaca cacatattca cacaacgaac ctgtatcagt 136080 ttaggagaaa gtgttacagaaaatatagct cctttaaagt aacttccaat cacaatactg 136140 aagtgataaa tccacttctgaaaagcaatt tttaaagatt cctaaaatac tcattttgac 136200 aacccacaaa attaaggtttttaagctatt aaacaaaata tgtcccaata taaacacaac 136260 tttcataggc caagttccatcccacagtaa atatgtggac aaaaatcaaa actcttcagt 136320 gtactccaat aataatttttaattaaacga gaggcatacc ataagaatta aaaaaagcct 136380 actaaacttc tggttttagggaattacagg ctttacactt ctgcaaagat gtgttttagt 136440 aaatgcaaga cgaagcactgaccaactatc atcacacatc agaatccttc caacaaaaaa 136500 cccaggactg aatttaaggaaaacaaaata aacgacagag ggggaaaaaa taatgtcttg 136560 ccacggtacc gcagcggctggatagcctgc ttgtgaaatg ctaatgccac ttcggagcag 136620 ttagtcacca gctattgtgtagggcaggag aaagccgagc cggccgcgcg tgcagagcga 136680 gcaagcgaac gagcgagcgcgctctccctc ttcgcgccgc tcccgccgcc gccgactctc 136740 gcgcgccccc gcgcccgcacggacgcgcgc gccggcccct cctcctccgg ccttgcactg 136800 cacaacactc atgacgtatctttatttcta gcacattaac aaaatatcac aaataaattg 136860 tccgcagccc ctgcggccccgaagtacgag tacccccggc cactggcccc cgcagacccc 136920 gcgccggcct cccaaccctccccatggcct ttggagcttt cacgttctag ggccaagttt 136980 ttgtctctgt aaaaaattgcgggaaattca atttttattc gactcaggga aaagtttctt 137040 tgctctgcga cgtgaatgtctcaccagatt ctggtaggtc ctgggatgct ccttcccggt 137100 ccagtcggtg cgccggggcagcagctgcgg ggagaggaca ccccgtgagc ccgcccccgg 137160 ccctacccgc cgtcccctccccgccgcccg gcccgcggtc cccgagcccc ggcccgcctc 137220 cgcgggcagg gcggcagggccagaggcgcc cgcgccgggg taccgcgggc cgcgccgctt 137280 acctccttct cggccacctcgcggatcagc acctgcaaca acaaagcggg gagagctgag 137340 ccccgcgccc cgggccgcggtccgccgtgc tcgcctccct cccccacgcc cgcgagcgcg 137400 agcgccggcc cggcccgcgccgcgcgccgc cgtacctgag ccgcctgctg acagggtcca 137460 tcttccagga accgggcgatgaggaagtag agctctgcgc gggagagagg gacggggaga 137520 cacacaggct gagcggtcgggcggcggggg gcgggggacc gcgggcggaa tcgcccggtg 137580 ccagcggccc cggcagccccccgacttacc cgatcgcagc tccgagaggc ctttcctctc 137640 acaagacatg tttatgggtcacttcagggc cgccgacggg acaccccgcc gccgagggga 137700 agcggggacg gtgccgccgcctgccctata gctgtcagtg tgtgttcacg agccgagctt 137760 cggctccacc attcaagcaacggcggcgga ggcggaggag gaggaggagg aaacaacaac 137820 tctcaggcag cgactacggccgtggccgcc tccgccgcgg atccctccgc cgcagaaagg 137880 agtccgccgc cttcgcggcccagggctcgg ccccggctct ggcccgcgcc cccgcccccc 137940 ggcgctaaaa aaggagtgcctccgacccct cgtccccagc gctccgcacg cggcacagtg 138000 agacccccac ccgctcctccccgcagggcg tgcgatttat ttatttattt ccagtcggag 138060 aagatgtcgg agcccaagccgccggttggc tggaaggcgc tttctctgtg gaggccgata 138120 gtggcaggga gggggccggggacggttccg cggagggatc tgacgcacac ggagccgcag 138180 cacaggctct attcagcggcgctggctgga gctgagatgg aagttagttt ctatgtagca 138240 gaaatatgaa acaaatgaagcaaaactgcc cagagagggg aaatgcccca aggatgggtc 138300 tcactcacgc gcgtacacagacacacacgc agagagcact ctcacgctgg gcaagctcgg 138360 gatcgcgcta cccttcccgagttgaatgat agtgtttggt ttctgtctct tgccatgtgc 138420 atgtgtataa atgctgcggattggcatctg tgtaagtctt gtcctgcgtt atttctgcag 138480 cctatgcaag tgttgtgtaatttattggag tgctgtatat tgcaatagag gtttgggctg 138540 ctttttgtta agcacttgcgttttgcaaac ccgttatttg ctgaagccac ctctgcatat 138600 ttcttttatt actgccattgcctttggcgt acgtttttta aatgtttttt attgttaaac 138660 gggcaaagcg aactcttgatttgtacttca gatactcttt ttccttatta caaaaaggct 138720 agtgatggct aattaggtatttggaattaa agaaccttaa agctttttta agtgtttacg 138780 agaagggaga atgtaaacctgagggaaagg aaaggacgct aatattcatg tctaactgat 138840 ctggaggtaa tttagtgacagatcgataac ctgcctaagg atattgaaag agtatactac 138900 agtttagcca aggtgaatagtgattaaata atttaaataa tctgtgtatc ttgcagttga 138960 cttcgtcatg ctaattaatggcttctaatt tgagatgtaa accattcctg tttacagtta 139020 atcacgggaa gacttcttgaaaactgacga aaaggagaaa aaaaaatctt tcgtaaatta 139080 gtatgtaatt accgattttatatgctaaat catacatctg tgttttgctg atgaggataa 139140 gggccttgtt tttaaaaaaacgaatatggg tgaaattaat ggaaacaata gaaaaagcca 139200 tttgttagaa aacaaggacaccaaatgata tttatctcca gatgatttaa gcactttcca 139260 aaaagacttg agagttcaatattttttaag gattgcattt taaagggaat ttggatagtc 139320 gttcttttgt taacatttaacaaaagattc tccttaaaaa tgttagataa taaactgcat 139380 tttatgggtc tggtttaaaaaggttatttg tggggaaagg accaacaagc tgtattgtgg 139440 ttttctagat tgtttcctcaagccttgtaa cctcctagct ccttacattc ctagtgggaa 139500 atacttgctg caaatgccttgggctgcact gtaagcccaa gtgtgctgca ccagtgtgat 139560 gccctatact aaaacatccagaaatcatca tacatatgag gaagaagaaa taaagcctca 139620 aaccctttgg aataataggatataaaattg ccttttgtaa ctgaatctta aaaatggaag 139680 gttaccatga cttgtcctattgcaacctgg ttatcagaat aacttatttt ttttaagata 139740 gctattctca aatactgaacatatttgcat ctttaaagac actttattct attcaattat 139800 aggtaaagta gcctatttctaggtggttag gcttgaaaag atagactgaa aagataggaa 139860 attttgtatg cctttttgcaaattgtattt acttctaaga ccgatgctgt tttagcttaa 139920 cttttaaaaa agtgttcttcaaataattgt aatattttac acgatcttga agttcttcaa 139980 ataaacagag tttagaaactaaaaattata gtgggatttt ctggttttga aggcttggaa 140040 70 2837 DNA Homosapiens 70 cgagattggc tgtggaagaa ctaactgaaa atggtttgac attagaagaatggttgccat 60 caacatggat tacagatacc attccccgaa gatgtccatt tgtgccacagatgggtgatg 120 aggtttatta tttccgacaa ggacatgaag cctatgtcga aatggcccggaaaaataaaa 180 tatatagtat caatcccaaa aaacaaccat ggcataaaat ggagctacgggaacaagaac 240 ttatgaaaat agttggcata aagtatgaag tgggattacc taccctttgctgccttaaac 300 ttgcttttct agatcctgat actggtaaac tgactggtgg atcatttaccatgaaatacc 360 atgatatgcc tgacgtcata gattttctag tcttgagaca acaatttgatgatgcaaaat 420 acaggcgatg gaatataggt gaccgcttca ggtctgtcat agatgatgcctggtggtttg 480 gaacaatcga aagccaggaa cctcttcaac ttgagtaccc tgatagtctgtttcaatgct 540 acaatgtttg ctgggacaat ggagatacag aaaagatgag tccttgggatatggagctta 600 tacctaataa tgctgtattt cctgaagaac taggtaccag tgttcctttaactgatggtg 660 agtgcagatc actaatctat aaacctcttg atggagaatg gggtaccaatcccagggatg 720 aagaatgtga aagaattgtg gcaggaataa accagttgat gacactagatattgcctcag 780 catttgtggc ccccgtggat ctgcaagcct atcccatgta ttgcacagtagtggcatatc 840 caacggatct aagtacaatt aaacaaagac tggaaaacag gttttacaggcgggtttctt 900 ccctaatgtg ggaagttcga tatatagagc ataatacacg aacatttaatgagcctggaa 960 gccctattgt gaaatctgct aaattcgtga ctgatcttct tctacattttataaaggatc 1020 agacttgtta taacataatt ccactttata attcaatgaa gaagaaagttttgtctgatt 1080 ctgaggatga agagaaagat gttgatgtgc caggaacttc tactcgaaaaaggaaggacc 1140 atcagcgtag aagaagatta cgtaatagag cccagtctta cgatattcaagcatggaaga 1200 accagtgtga agaattgtta aatctcatat ttcaatgtga agattcagagcctttccgtc 1260 agccggtaga tctccttgaa tatccagact acagagacat cattgacactccaatggatt 1320 ttgctaccgt tagagaaact ttagaggctg ggaattatga gtcaccaatggagttatgta 1380 aagatgtcag acttattttc agtaattcca aagcatatac accaagcaaaagatcaagga 1440 tttacagcat gagtttgcgc ctgtctgctt tctttgaaga acacattagttcagttttat 1500 cagattataa atctgctctt cgttttcata aaagaaatac cataaccaaaaggaggaaga 1560 aaagaaacag aagcagctct gtttccagta gtgctgcatc aagccctgaaaggaaaaaaa 1620 ggatcttaaa accccagcta aaatcagaaa gctctacctc tgcattctctacacctacac 1680 gatcaatacc gccaagacac aatgctgctc agataaacgg taaaacagaatctagttctg 1740 tggttcgaac cagaagcaac cgagtggttg tagatccagt tgtcactgagcaaccatcta 1800 cttcttcagc tgcaaagact tttattacaa aagctaatgc atctgcaataccagggaaaa 1860 caatactaga gaattctgtg aaacattcca aagctttgaa tactctttccagtcctggtc 1920 aatccagttt tagtcatggc actaggaata attctgcaaa agaaaacatggaaaaggaaa 1980 agccagtcaa acgtaaaatg aagtcatctg tactcccaaa ggcgtccactctttcaaagt 2040 catcagctgt cattgagcaa ggagattgta agaacaacgc tcttgtaccaggaaccattc 2100 aagtaaatgg ccatggagga cagccatcaa aacttgtgaa gaggggacctggaaggaaac 2160 ctaaagtaga agttaatacc aatagtggtg aaattataca caagaaaaggggtagaaagc 2220 ccaaaaagct acagtatgca aagccagaag atttagagca aaataatgtgcatcccatca 2280 gagatgaagt acttccttct tcaacatgca attttctttc tgaaactaataatgtaaagg 2340 aagatttgtt acagaaaaag aatcgtggag gtaggaagcc caaaaggaagatgaagacac 2400 aaaaattaga tgcagatctc ctagtccctg caagtgtcaa agtgttaaggagaagtaacc 2460 cgaaaaaaat agatgatcct atagatgagg aagaagagtt tgaagaactcaaaggctctg 2520 aaccccacat gagaactaga aatcaaggtc gaaggacagc tttctataatgaggatgact 2580 ctgaagagga gcaaaggcag ctgttgttcg aagacacctc tttaacttttggaacttcta 2640 gtagaggacg agtccgaaag ttgactgaaa aagcaaaagc taatttaattggttggtaac 2700 ttgtaccaaa atattttact tcaaaatcta taaagcaggt acagttaaggaataagtagg 2760 actaaggctt ctgcttcctt gctgctgtgg tggagtaggg aatgttatgatttgatttgc 2820 aaaaaaaaaa aaaaaag 2837 71 898 PRT Homo sapiens 71 ArgLeu Ala Val Glu Glu Leu Thr Glu Asn Gly Leu Thr Leu Glu Glu 1 5 10 15Trp Leu Pro Ser Thr Trp Ile Thr Asp Thr Ile Pro Arg Arg Cys Pro 20 25 30Phe Val Pro Gln Met Gly Asp Glu Val Tyr Tyr Phe Arg Gln Gly His 35 40 45Glu Ala Tyr Val Glu Met Ala Arg Lys Asn Lys Ile Tyr Ser Ile Asn 50 55 60Pro Lys Lys Gln Pro Trp His Lys Met Glu Leu Arg Glu Gln Glu Leu 65 70 7580 Met Lys Ile Val Gly Ile Lys Tyr Glu Val Gly Leu Pro Thr Leu Cys 85 9095 Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp Thr Gly Lys Leu Thr Gly 100105 110 Gly Ser Phe Thr Met Lys Tyr His Asp Met Pro Asp Val Ile Asp Phe115 120 125 Leu Val Leu Arg Gln Gln Phe Asp Asp Ala Lys Tyr Arg Arg TrpAsn 130 135 140 Ile Gly Asp Arg Phe Arg Ser Val Ile Asp Asp Ala Trp TrpPhe Gly 145 150 155 160 Thr Ile Glu Ser Gln Glu Pro Leu Gln Leu Glu TyrPro Asp Ser Leu 165 170 175 Phe Gln Cys Tyr Asn Val Cys Trp Asp Asn GlyAsp Thr Glu Lys Met 180 185 190 Ser Pro Trp Asp Met Glu Leu Ile Pro AsnAsn Ala Val Phe Pro Glu 195 200 205 Glu Leu Gly Thr Ser Val Pro Leu ThrAsp Gly Glu Cys Arg Ser Leu 210 215 220 Ile Tyr Lys Pro Leu Asp Gly GluTrp Gly Thr Asn Pro Arg Asp Glu 225 230 235 240 Glu Cys Glu Arg Ile ValAla Gly Ile Asn Gln Leu Met Thr Leu Asp 245 250 255 Ile Ala Ser Ala PheVal Ala Pro Val Asp Leu Gln Ala Tyr Pro Met 260 265 270 Tyr Cys Thr ValVal Ala Tyr Pro Thr Asp Leu Ser Thr Ile Lys Gln 275 280 285 Arg Leu GluAsn Arg Phe Tyr Arg Arg Val Ser Ser Leu Met Trp Glu 290 295 300 Val ArgTyr Ile Glu His Asn Thr Arg Thr Phe Asn Glu Pro Gly Ser 305 310 315 320Pro Ile Val Lys Ser Ala Lys Phe Val Thr Asp Leu Leu Leu His Phe 325 330335 Ile Lys Asp Gln Thr Cys Tyr Asn Ile Ile Pro Leu Tyr Asn Ser Met 340345 350 Lys Lys Lys Val Leu Ser Asp Ser Glu Asp Glu Glu Lys Asp Val Asp355 360 365 Val Pro Gly Thr Ser Thr Arg Lys Arg Lys Asp His Gln Arg ArgArg 370 375 380 Arg Leu Arg Asn Arg Ala Gln Ser Tyr Asp Ile Gln Ala TrpLys Asn 385 390 395 400 Gln Cys Glu Glu Leu Leu Asn Leu Ile Phe Gln CysGlu Asp Ser Glu 405 410 415 Pro Phe Arg Gln Pro Val Asp Leu Leu Glu TyrPro Asp Tyr Arg Asp 420 425 430 Ile Ile Asp Thr Pro Met Asp Phe Ala ThrVal Arg Glu Thr Leu Glu 435 440 445 Ala Gly Asn Tyr Glu Ser Pro Met GluLeu Cys Lys Asp Val Arg Leu 450 455 460 Ile Phe Ser Asn Ser Lys Ala TyrThr Pro Ser Lys Arg Ser Arg Ile 465 470 475 480 Tyr Ser Met Ser Leu ArgLeu Ser Ala Phe Phe Glu Glu His Ile Ser 485 490 495 Ser Val Leu Ser AspTyr Lys Ser Ala Leu Arg Phe His Lys Arg Asn 500 505 510 Thr Ile Thr LysArg Arg Lys Lys Arg Asn Arg Ser Ser Ser Val Ser 515 520 525 Ser Ser AlaAla Ser Ser Pro Glu Arg Lys Lys Arg Ile Leu Lys Pro 530 535 540 Gln LeuLys Ser Glu Ser Ser Thr Ser Ala Phe Ser Thr Pro Thr Arg 545 550 555 560Ser Ile Pro Pro Arg His Asn Ala Ala Gln Ile Asn Gly Lys Thr Glu 565 570575 Ser Ser Ser Val Val Arg Thr Arg Ser Asn Arg Val Val Val Asp Pro 580585 590 Val Val Thr Glu Gln Pro Ser Thr Ser Ser Ala Ala Lys Thr Phe Ile595 600 605 Thr Lys Ala Asn Ala Ser Ala Ile Pro Gly Lys Thr Ile Leu GluAsn 610 615 620 Ser Val Lys His Ser Lys Ala Leu Asn Thr Leu Ser Ser ProGly Gln 625 630 635 640 Ser Ser Phe Ser His Gly Thr Arg Asn Asn Ser AlaLys Glu Asn Met 645 650 655 Glu Lys Glu Lys Pro Val Lys Arg Lys Met LysSer Ser Val Leu Pro 660 665 670 Lys Ala Ser Thr Leu Ser Lys Ser Ser AlaVal Ile Glu Gln Gly Asp 675 680 685 Cys Lys Asn Asn Ala Leu Val Pro GlyThr Ile Gln Val Asn Gly His 690 695 700 Gly Gly Gln Pro Ser Lys Leu ValLys Arg Gly Pro Gly Arg Lys Pro 705 710 715 720 Lys Val Glu Val Asn ThrAsn Ser Gly Glu Ile Ile His Lys Lys Arg 725 730 735 Gly Arg Lys Pro LysLys Leu Gln Tyr Ala Lys Pro Glu Asp Leu Glu 740 745 750 Gln Asn Asn ValHis Pro Ile Arg Asp Glu Val Leu Pro Ser Ser Thr 755 760 765 Cys Asn PheLeu Ser Glu Thr Asn Asn Val Lys Glu Asp Leu Leu Gln 770 775 780 Lys LysAsn Arg Gly Gly Arg Lys Pro Lys Arg Lys Met Lys Thr Gln 785 790 795 800Lys Leu Asp Ala Asp Leu Leu Val Pro Ala Ser Val Lys Val Leu Arg 805 810815 Arg Ser Asn Pro Lys Lys Ile Asp Asp Pro Ile Asp Glu Glu Glu Glu 820825 830 Phe Glu Glu Leu Lys Gly Ser Glu Pro His Met Arg Thr Arg Asn Gln835 840 845 Gly Arg Arg Thr Ala Phe Tyr Asn Glu Asp Asp Ser Glu Glu GluGln 850 855 860 Arg Gln Leu Leu Phe Glu Asp Thr Ser Leu Thr Phe Gly ThrSer Ser 865 870 875 880 Arg Gly Arg Val Arg Lys Leu Thr Glu Lys Ala LysAla Asn Leu Ile 885 890 895 Gly Trp 72 3892 DNA Mus musculus 72gggggggggg gctagaagag tttttagttt tgtctgttag gatgtctttt gagagttttg 60taaagaatat acgttttgct tttgtctcta gccctccatc agtgattagg aaaagctgaa 120taactttcgt cacttctgct gcttttctag taaaaggttt taatactgga gagtaaaatt 180tttgcacaga tttatttcct tgtgtttgaa gatagtacta atgctgttgc atgctttctc 240agagattggc tgtaggagaa ctaactgaga atggcctaac gttagaagag tggttgcctt 300cagcttggat tacagacaca cttcccagga gatgtccatt tgtgccacag atgggtgatg 360aggtttatta ttttcgacaa gggcatgaag catatgttga gatggcccgg aaaaataaaa 420tttatagtat caatcctaaa aagcagccat ggcataagat ggaactaagg gaacaagaac 480taatgaaaat tgttggtata aagtatgaag tggggttgcc taccctttgc tgccttaaac 540ttgcttttct agatcctgat actggcaaac tgaccggtgg atcatttacc atgaaatacc 600atgatatgcc tgacgtcata gattttctag tcttgagaca acaatttgat gatgcaaagt 660atagacgatg gaatataggt gaccgcttca gatctgtcat agatgatgcc tggtggtttg 720gaacaattga aagtcaagag cctcttcaac ctgagtaccc tgatagtttg tttcagtgtt 780ataatgtatg ttgggacaat ggagatacag aaaagatgag tccttgggat atggaattaa 840tacctaataa tgctgtcttt ccagaagaac tgggtaccag tgttccttta actgatgttg 900aatgtaggtc gctaatttat aaacctcttg atggagattg gggagccaat cccagggatg 960aagaatgtga aagaattgtt ggaggaataa atcagctgat gacactagat attgcgtctg 1020catttgttgc ccctgtggac cttcaagctt atcccatgta ttgcactgtg gtggcctatc 1080caacggatct aagtacaatt aaacaaagac tggagaacag gttttacagg cgcttttcat 1140cactaatgtg ggaagttcga tatatagaac ataatacacg aacattcaat gagccaggaa 1200gcccaattgt gaaatctgct aaatttgtga ctgatcttct cctgcatttt ataaaggatc 1260agacttgtta taacataatt ccactttaca actcaatgaa gaagaaagtt ttgtctgact 1320ctgaggaaga agagaaagat gctgatgttc cagggacttc taccagaaag cgcaaggatc 1380atcaacctag aagaaggtta cgcaacagag ctcagtctta cgatattcag gcatggaaga 1440aacaatgtca agaattactg aatctcatat ttcaatgtga agactcagaa ccttttcgac 1500agccagtgga tcttcttgaa tatccagact accgagacat cattgacact ccaatggact 1560ttgccactgt tagagagact ttagaggctg ggaattatga gtcacccatg gagttatgta 1620aagatgtcag gctcattttc agtaattcta aagcatacac accaagcaag agatcaagga 1680tttacagcat gagtttacgc ctgtctgctt tctttgaaga acatattagt tcagttttgt 1740cagattataa atctgctctt cgttttcata aaagaaacac cataagcaag aagaggaaga 1800agcgaaacag gagcagctcc ctgtccagca gtgctgcctc aagccctgaa aggaaaaaaa 1860ggatcttaaa accccagcta aagtcagaag tatctacctc tccattctcc atacctacaa 1920gatcagtact accaagacat aatgctgcac aaatgaatgg taaaccagaa tccagttctg 1980tggttcgaac taggagcaac cgtgtagctg tagatccagt tgtcaccgag cagccctcta 2040catcatcagc cacaaaagct tttgtttcaa aaactaatac atctgccatg ccaggaaaag 2100caatgctaga gaattctgtg agacattcca aagccttgag cacactttcc agccctgatc 2160cgctcacatt cagccatgct acaaagaata attctgcaaa agaaaacatg gaaaaggaaa 2220agcctgtcaa acgtaaaatg aagtcttctg tgttttcaaa agcatctcca cttccaaagt 2280cagccgcagt catagagcaa ggagagtgta agaacaatgt tcttatacca ggaaccattc 2340aagtaaatgg ccatggagga caaccatcaa aactcgtgaa gagaggacct gggaggaagc 2400ccaaggtaga agttaacacc agcagtggtg aagtgacaca caagaaaaga ggtagaaagc 2460ccaagaatct gcagtgtgca aagcaggaaa actctgagca aaataacatg catcccatca 2520gggctgacgt gcttccttct tcaacatgca acttcctttc tgaaactaat gctgtcaagg 2580aggatttgtt acagaaaaag agtcgtggag gcagaaaacc caaaaggaag atgaaaactc 2640acaacctaga ttcagaactc atagttccta caaatgttaa agtgttaagg agaagtaacc 2700ggaaaaaaac agatgatcct atagatgagg aagaggagtt tgaagaactc aaaggctctg 2760agcctcacat gagaactaga aatcagggtc gaaggacaac tttctataat gaggatgact 2820ccgaggaaga acagagacag ctgttgttcg aggacacctc cttgacattt ggaacttcta 2880gtagaggacg agtccgaaag ttgactgaaa aagcaaaggc taatttaatt ggttggtaac 2940ttgaagcaaa atattgcatt ttaaaaaatc tgtaacgcag gtacagttaa ggagtaagta 3000gaactaaggt ctctgcttcc ttgctgctat gacggattag ggaatgttac aatttgactt 3060gggaaaatgg acaaaaacac atttagaaga taatttacat ctttgaatga aaaaaatcta 3120tatacatata tatttcaaat gtttgctatt tattgccctt aggtaggtta ttcggttcca 3180cattcatttc atttgctgtt tgaaattgag gacctgttat aaattctggt ttatttatgg 3240aagagacagc tctgctacac tattaagaaa catagtattc ctagagataa agtatgttcc 3300ctcttaaatt gagttatttt tgaccaagtg aggtacattt ttactgatag cagaaggcat 3360gccctaggaa gagagatgtt acaaagagta gcagtacatt aagaatggct tcctctaaag 3420ataactttcc agttcccacc atttggtatc ctgaaaagtg ttgtgaactg taggtgttca 3480attacagaat atctagagga agcttttgtt ttactccatt tctgccaaac ttaggagaaa 3540aatgtattga tgcaaaggaa acatatccac attggaaaac atttgactgt ctaatttttc 3600agaccttgat tcttatatca gtcactctat ctctgtttat tgtgccaaag actgagaatc 3660agtgcagtgg aaagcctgtt tttgactgtc aggacagcat acacttttca gtactggaaa 3720agctatatat tctaaagagc aagttattac aaaattatgc tgagttatat cctttttttg 3780gtactaaatg taggaaaata atgcactggt gggtcctttg acagagatat cttagagaaa 3840aaaaaaaaaa aggaattcga tatcaagctt atcgataccg tcgacctcga gg 3892 73 902PRT Mus musculus 73 Met Leu Ser Gln Arg Leu Ala Val Gly Glu Leu Thr GluAsn Gly Leu 1 5 10 15 Thr Leu Glu Glu Trp Leu Pro Ser Ala Trp Ile ThrAsp Thr Leu Pro 20 25 30 Arg Arg Cys Pro Phe Val Pro Gln Met Gly Asp GluVal Tyr Tyr Phe 35 40 45 Arg Gln Gly His Glu Ala Tyr Val Glu Met Ala ArgLys Asn Lys Ile 50 55 60 Tyr Ser Ile Asn Pro Lys Lys Gln Pro Trp His LysMet Glu Leu Arg 65 70 75 80 Glu Gln Glu Leu Met Lys Ile Val Gly Ile LysTyr Glu Val Gly Leu 85 90 95 Pro Thr Leu Cys Cys Leu Lys Leu Ala Phe LeuAsp Pro Asp Thr Gly 100 105 110 Lys Leu Thr Gly Gly Ser Phe Thr Met LysTyr His Asp Met Pro Asp 115 120 125 Val Ile Asp Phe Leu Val Leu Arg GlnGln Phe Asp Asp Ala Lys Tyr 130 135 140 Arg Arg Trp Asn Ile Gly Asp ArgPhe Arg Ser Val Ile Asp Asp Ala 145 150 155 160 Trp Trp Phe Gly Thr IleGlu Ser Gln Glu Pro Leu Gln Pro Glu Tyr 165 170 175 Pro Asp Ser Leu PheGln Cys Tyr Asn Val Cys Trp Asp Asn Gly Asp 180 185 190 Thr Glu Lys MetSer Pro Trp Asp Met Glu Leu Ile Pro Asn Asn Ala 195 200 205 Val Phe ProGlu Glu Leu Gly Thr Ser Val Pro Leu Thr Asp Val Glu 210 215 220 Cys ArgSer Leu Ile Tyr Lys Pro Leu Asp Gly Asp Trp Gly Ala Asn 225 230 235 240Pro Arg Asp Glu Glu Cys Glu Arg Ile Val Gly Gly Ile Asn Gln Leu 245 250255 Met Thr Leu Asp Ile Ala Ser Ala Phe Val Ala Pro Val Asp Leu Gln 260265 270 Ala Tyr Pro Met Tyr Cys Thr Val Val Ala Tyr Pro Thr Asp Leu Ser275 280 285 Thr Ile Lys Gln Arg Leu Glu Asn Arg Phe Tyr Arg Arg Phe SerSer 290 295 300 Leu Met Trp Glu Val Arg Tyr Ile Glu His Asn Thr Arg ThrPhe Asn 305 310 315 320 Glu Pro Gly Ser Pro Ile Val Lys Ser Ala Lys PheVal Thr Asp Leu 325 330 335 Leu Leu His Phe Ile Lys Asp Gln Thr Cys TyrAsn Ile Ile Pro Leu 340 345 350 Tyr Asn Ser Met Lys Lys Lys Val Leu SerAsp Ser Glu Glu Glu Glu 355 360 365 Lys Asp Ala Asp Val Pro Gly Thr SerThr Arg Lys Arg Lys Asp His 370 375 380 Gln Pro Arg Arg Arg Leu Arg AsnArg Ala Gln Ser Tyr Asp Ile Gln 385 390 395 400 Ala Trp Lys Lys Gln CysGln Glu Leu Leu Asn Leu Ile Phe Gln Cys 405 410 415 Glu Asp Ser Glu ProPhe Arg Gln Pro Val Asp Leu Leu Glu Tyr Pro 420 425 430 Asp Tyr Arg AspIle Ile Asp Thr Pro Met Asp Phe Ala Thr Val Arg 435 440 445 Glu Thr LeuGlu Ala Gly Asn Tyr Glu Ser Pro Met Glu Leu Cys Lys 450 455 460 Asp ValArg Leu Ile Phe Ser Asn Ser Lys Ala Tyr Thr Pro Ser Lys 465 470 475 480Arg Ser Arg Ile Tyr Ser Met Ser Leu Arg Leu Ser Ala Phe Phe Glu 485 490495 Glu His Ile Ser Ser Val Leu Ser Asp Tyr Lys Ser Ala Leu Arg Phe 500505 510 His Lys Arg Asn Thr Ile Ser Lys Lys Arg Lys Lys Arg Asn Arg Ser515 520 525 Ser Ser Leu Ser Ser Ser Ala Ala Ser Ser Pro Glu Arg Lys LysArg 530 535 540 Ile Leu Lys Pro Gln Leu Lys Ser Glu Val Ser Thr Ser ProPhe Ser 545 550 555 560 Ile Pro Thr Arg Ser Val Leu Pro Arg His Asn AlaAla Gln Met Asn 565 570 575 Gly Lys Pro Glu Ser Ser Ser Val Val Arg ThrArg Ser Asn Arg Val 580 585 590 Ala Val Asp Pro Val Val Thr Glu Gln ProSer Thr Ser Ser Ala Thr 595 600 605 Lys Ala Phe Val Ser Lys Thr Asn ThrSer Ala Met Pro Gly Lys Ala 610 615 620 Met Leu Glu Asn Ser Val Arg HisSer Lys Ala Leu Ser Thr Leu Ser 625 630 635 640 Ser Pro Asp Pro Leu ThrPhe Ser His Ala Thr Lys Asn Asn Ser Ala 645 650 655 Lys Glu Asn Met GluLys Glu Lys Pro Val Lys Arg Lys Met Lys Ser 660 665 670 Ser Val Phe SerLys Ala Ser Pro Leu Pro Lys Ser Ala Ala Val Ile 675 680 685 Glu Gln GlyGlu Cys Lys Asn Asn Val Leu Ile Pro Gly Thr Ile Gln 690 695 700 Val AsnGly His Gly Gly Gln Pro Ser Lys Leu Val Lys Arg Gly Pro 705 710 715 720Gly Arg Lys Pro Lys Val Glu Val Asn Thr Ser Ser Gly Glu Val Thr 725 730735 His Lys Lys Arg Gly Arg Lys Pro Lys Asn Leu Gln Cys Ala Lys Gln 740745 750 Glu Asn Ser Glu Gln Asn Asn Met His Pro Ile Arg Ala Asp Val Leu755 760 765 Pro Ser Ser Thr Cys Asn Phe Leu Ser Glu Thr Asn Ala Val LysGlu 770 775 780 Asp Leu Leu Gln Lys Lys Ser Arg Gly Gly Arg Lys Pro LysArg Lys 785 790 795 800 Met Lys Thr His Asn Leu Asp Ser Glu Leu Ile ValPro Thr Asn Val 805 810 815 Lys Val Leu Arg Arg Ser Asn Arg Lys Lys ThrAsp Asp Pro Ile Asp 820 825 830 Glu Glu Glu Glu Phe Glu Glu Leu Lys GlySer Glu Pro His Met Arg 835 840 845 Thr Arg Asn Gln Gly Arg Arg Thr ThrPhe Tyr Asn Glu Asp Asp Ser 850 855 860 Glu Glu Glu Gln Arg Gln Leu LeuPhe Glu Asp Thr Ser Leu Thr Phe 865 870 875 880 Gly Thr Ser Ser Arg GlyArg Val Arg Lys Leu Thr Glu Lys Ala Lys 885 890 895 Ala Asn Leu Ile GlyTrp 900 74 3264 DNA Homo sapiens 74 cggatcttgg agaatccaaa aagcaacagacaaatcaaca caattatcgt acaagatctg 60 cattggaaga gactcctaga ccctcagaagagatagaaaa tggcagtagt tcttcagatg 120 aaggcgaagt agttgctgtc agtggtggaacatccgaaga agaagagaga gcatggcaca 180 gtgatggcag ttctagtgac tactccagtgattactctga ctggacagca gatgcaggaa 240 ttaatctgca gccaccaaag aaagttcctaagaataaaac caagaaagca gaaagcagtt 300 cagatgaaga agaagaatct gaaaaacagaagcaaaaaca gattaaaaag ggaaaagaaa 360 aagcaaatga agaaaaagat ggaccaatatcaccaaagaa aaagaaagcc caaagaaaga 420 aaacaaaaga gattggctgt ggaagaactaactgaaaatg gtttgacatt agaagaatgg 480 ttgccatcaa catggattac agataccattccccgaagat gtccatttgt gccacagatg 540 ggtgatgagg tttattattt ccgacaaggacatgaagcct atgtcgaaat ggcccggaaa 600 aataaaatat atagtatcaa tcccaaaaaacaaccatggc ataaaatgga gctacgggaa 660 caagaactta tgaaaatagt tggcataaagtatgaagtgg gattacctac cctttgctgc 720 cttaaacttg cttttctaga tcctgatactggtaaactga ctggtggatc atttaccatg 780 aaataccatg atatgcctga cgtcatagattttctagtct tgagacaaca atttgatgat 840 gcaaaataca ggcgatggaa tataggtgaccgcttcaggt ctgtcataga tgatgcctgg 900 tggtttggaa caatcgaaag ccaggaacctcttcaacttg agtaccctga tagtctgttt 960 caatgctaca atgtttgctg ggacaatggagatacagaaa agatgagtcc ttgggatatg 1020 gagcttatac ctaataatgc tgtatttcctgaagaactag gtaccagtgt tcctttaact 1080 gatggtgagt gcagatcact aatctataaacctcttgatg gagaatgggg taccaatccc 1140 agggatgaag aatgtgaaag aattgtggcaggaataaacc agttgatgac actagatatt 1200 gcctcagcat ttgtggcccc cgtggatctgcaagcctatc ccatgtattg cacagtagtg 1260 gcatatccaa cggatctaag tacaattaaacaaagactgg aaaacaggtt ttacaggcgg 1320 gtttcttccc taatgtggga agttcgatatatagagcata atacacgaac atttaatgag 1380 cctggaagcc ctattgtgaa atctgctaaattcgtgactg atcttcttct acattttata 1440 aaggatcaga cttgttataa cataattccactttataatt caatgaagaa gaaagttttg 1500 tctgattctg aggatgaaga gaaagatgttgatgtgccag gaacttctac tcgaaaaagg 1560 aaggaccatc agcgtagaag aagattacgtaatagagccc agtcttacga tattcaagca 1620 tggaagaacc agtgtgaaga attgttaaatctcatatttc aatgtgaaga ttcagagcct 1680 ttccgtcagc cggtagatct ccttgaatatccagactaca gagacatcat tgacactcca 1740 atggattttg ctaccgttag agaaactttagaggctggga attatgagtc accaatggag 1800 ttatgtaaag atgtcagact tattttcagtaattccaaag catatacacc aagcaaaaga 1860 tcaaggattt acagcatgag tttgcgcctgtctgctttct ttgaagaaca cattagttca 1920 gttttatcag attataaatc tgctcttcgttttcataaaa gaaataccat aaccaaaagg 1980 aggaagaaaa gaaacagaag cagctctgtttccagtagtg ctgcatcaag ccctgaaagg 2040 aaaaaaagga tcttaaaacc ccagctaaaatcagaaagct ctacctctgc attctctaca 2100 cctacacgat caataccgcc aagacacaatgctgctcaga taaacggtaa aacagaatct 2160 agttctgtgg ttcgaaccag aagcaaccgagtggttgtag atccagttgt cactgagcaa 2220 ccatctactt cttcagctgc aaagacttttattacaaaag ctaatgcatc tgcaatacca 2280 gggaaaacaa tactagagaa ttctgtgaaacattccaaag ctttgaatac tctttccagt 2340 cctggtcaat ccagttttag tcatggcactaggaataatt ctgcaaaaga aaacatggaa 2400 aaggaaaagc cagtcaaacg taaaatgaagtcatctgtac tcccaaaggc gtccactctt 2460 tcaaagtcat cagctgtcat tgagcaaggagattgtaaga acaacgctct tgtaccagga 2520 accattcaag taaatggcca tggaggacagccatcaaaac ttgtgaagag gggacctgga 2580 aggaaaccta aagtagaagt taataccaatagtggtgaaa ttatacacaa gaaaaggggt 2640 agaaagccca aaaagctaca gtatgcaaagccagaagatt tagagcaaaa taatgtgcat 2700 cccatcagag atgaagtact tccttcttcaacatgcaatt ttctttctga aactaataat 2760 gtaaaggaag atttgttaca gaaaaagaatcgtggaggta ggaagcccaa aaggaagatg 2820 aagacacaaa aattagatgc agatctcctagtccctgcaa gtgtcaaagt gttaaggaga 2880 agtaacccga aaaaaataga tgatcctatagatgaggaag aagagtttga agaactcaaa 2940 ggctctgaac cccacatgag aactagaaatcaaggtcgaa ggacagcttt ctataatgag 3000 gatgactctg aagaggagca aaggcagctgttgttcgaag acacctcttt aacttttgga 3060 acttctagta gaggacgagt ccgaaagttgactgaaaaag caaaagctaa tttaattggt 3120 tggtaacttg taccaaaata ttttacttcaaaatctataa agcaggtaca gttaaggaat 3180 aagtaggact aaggcttctg cttccttgctgctgtggtgg agtagggaat gttatgattt 3240 gatttgcaaa aaaaaaaaaa aaag 3264 751039 PRT Homo sapiens 75 Arg Ile Leu Glu Asn Pro Lys Ser Asn Arg Gln IleAsn Thr Ile Ile 1 5 10 15 Val Gln Asp Leu His Trp Lys Arg Leu Leu AspPro Gln Lys Arg Lys 20 25 30 Met Ala Val Val Leu Gln Met Lys Ala Lys LeuLeu Ser Val Val Glu 35 40 45 His Pro Lys Lys Lys Arg Glu His Gly Thr ValMet Ala Val Leu Val 50 55 60 Thr Thr Pro Val Ile Thr Leu Thr Gly Gln GlnMet Gln Glu Leu Ile 65 70 75 80 Cys Ser His Gln Arg Lys Phe Leu Arg IleLys Pro Arg Lys Gln Lys 85 90 95 Ala Val Gln Met Lys Lys Lys Asn Leu LysAsn Arg Ser Lys Asn Arg 100 105 110 Leu Lys Arg Glu Lys Lys Lys Gln MetLys Lys Lys Met Asp Gln Tyr 115 120 125 His Gln Arg Lys Arg Lys Pro LysGlu Arg Lys Gln Lys Arg Leu Ala 130 135 140 Val Glu Glu Leu Thr Glu AsnGly Leu Thr Leu Glu Glu Trp Leu Pro 145 150 155 160 Ser Thr Trp Ile ThrAsp Thr Ile Pro Arg Arg Cys Pro Phe Val Pro 165 170 175 Gln Met Gly AspGlu Val Tyr Tyr Phe Arg Gln Gly His Glu Ala Tyr 180 185 190 Val Glu MetAla Arg Lys Asn Lys Ile Tyr Ser Ile Asn Pro Lys Lys 195 200 205 Gln ProTrp His Lys Met Glu Leu Arg Glu Gln Glu Leu Met Lys Ile 210 215 220 ValGly Ile Lys Tyr Glu Val Gly Leu Pro Thr Leu Cys Cys Leu Lys 225 230 235240 Leu Ala Phe Leu Asp Pro Asp Thr Gly Lys Leu Thr Gly Gly Ser Phe 245250 255 Thr Met Lys Tyr His Asp Met Pro Asp Val Ile Asp Phe Leu Val Leu260 265 270 Arg Gln Gln Phe Asp Asp Ala Lys Tyr Arg Arg Trp Asn Ile GlyAsp 275 280 285 Arg Phe Arg Ser Val Ile Asp Asp Ala Trp Trp Phe Gly ThrIle Glu 290 295 300 Ser Gln Glu Pro Leu Gln Leu Glu Tyr Pro Asp Ser LeuPhe Gln Cys 305 310 315 320 Tyr Asn Val Cys Trp Asp Asn Gly Asp Thr GluLys Met Ser Pro Trp 325 330 335 Asp Met Glu Leu Ile Pro Asn Asn Ala ValPhe Pro Glu Glu Leu Gly 340 345 350 Thr Ser Val Pro Leu Thr Asp Gly GluCys Arg Ser Leu Ile Tyr Lys 355 360 365 Pro Leu Asp Gly Glu Trp Gly ThrAsn Pro Arg Asp Glu Glu Cys Glu 370 375 380 Arg Ile Val Ala Gly Ile AsnGln Leu Met Thr Leu Asp Ile Ala Ser 385 390 395 400 Ala Phe Val Ala ProVal Asp Leu Gln Ala Tyr Pro Met Tyr Cys Thr 405 410 415 Val Val Ala TyrPro Thr Asp Leu Ser Thr Ile Lys Gln Arg Leu Glu 420 425 430 Asn Arg PheTyr Arg Arg Val Ser Ser Leu Met Trp Glu Val Arg Tyr 435 440 445 Ile GluHis Asn Thr Arg Thr Phe Asn Glu Pro Gly Ser Pro Ile Val 450 455 460 LysSer Ala Lys Phe Val Thr Asp Leu Leu Leu His Phe Ile Lys Asp 465 470 475480 Gln Thr Cys Tyr Asn Ile Ile Pro Leu Tyr Asn Ser Met Lys Lys Lys 485490 495 Val Leu Ser Asp Ser Glu Asp Glu Glu Lys Asp Val Asp Val Pro Gly500 505 510 Thr Ser Thr Arg Lys Arg Lys Asp His Gln Arg Arg Arg Arg LeuArg 515 520 525 Asn Arg Ala Gln Ser Tyr Asp Ile Gln Ala Trp Lys Asn GlnCys Glu 530 535 540 Glu Leu Leu Asn Leu Ile Phe Gln Cys Glu Asp Ser GluPro Phe Arg 545 550 555 560 Gln Pro Val Asp Leu Leu Glu Tyr Pro Asp TyrArg Asp Ile Ile Asp 565 570 575 Thr Pro Met Asp Phe Ala Thr Val Arg GluThr Leu Glu Ala Gly Asn 580 585 590 Tyr Glu Ser Pro Met Glu Leu Cys LysAsp Val Arg Leu Ile Phe Ser 595 600 605 Asn Ser Lys Ala Tyr Thr Pro SerLys Arg Ser Arg Ile Tyr Ser Met 610 615 620 Ser Leu Arg Leu Ser Ala PhePhe Glu Glu His Ile Ser Ser Val Leu 625 630 635 640 Ser Asp Tyr Lys SerAla Leu Arg Phe His Lys Arg Asn Thr Ile Thr 645 650 655 Lys Arg Arg LysLys Arg Asn Arg Ser Ser Ser Val Ser Ser Ser Ala 660 665 670 Ala Ser SerPro Glu Arg Lys Lys Arg Ile Leu Lys Pro Gln Leu Lys 675 680 685 Ser GluSer Ser Thr Ser Ala Phe Ser Thr Pro Thr Arg Ser Ile Pro 690 695 700 ProArg His Asn Ala Ala Gln Ile Asn Gly Lys Thr Glu Ser Ser Ser 705 710 715720 Val Val Arg Thr Arg Ser Asn Arg Val Val Val Asp Pro Val Val Thr 725730 735 Glu Gln Pro Ser Thr Ser Ser Ala Ala Lys Thr Phe Ile Thr Lys Ala740 745 750 Asn Ala Ser Ala Ile Pro Gly Lys Thr Ile Leu Glu Asn Ser ValLys 755 760 765 His Ser Lys Ala Leu Asn Thr Leu Ser Ser Pro Gly Gln SerSer Phe 770 775 780 Ser His Gly Thr Arg Asn Asn Ser Ala Lys Glu Asn MetGlu Lys Glu 785 790 795 800 Lys Pro Val Lys Arg Lys Met Lys Ser Ser ValLeu Pro Lys Ala Ser 805 810 815 Thr Leu Ser Lys Ser Ser Ala Val Ile GluGln Gly Asp Cys Lys Asn 820 825 830 Asn Ala Leu Val Pro Gly Thr Ile GlnVal Asn Gly His Gly Gly Gln 835 840 845 Pro Ser Lys Leu Val Lys Arg GlyPro Gly Arg Lys Pro Lys Val Glu 850 855 860 Val Asn Thr Asn Ser Gly GluIle Ile His Lys Lys Arg Gly Arg Lys 865 870 875 880 Pro Lys Lys Leu GlnTyr Ala Lys Pro Glu Asp Leu Glu Gln Asn Asn 885 890 895 Val His Pro IleArg Asp Glu Val Leu Pro Ser Ser Thr Cys Asn Phe 900 905 910 Leu Ser GluThr Asn Asn Val Lys Glu Asp Leu Leu Gln Lys Lys Asn 915 920 925 Arg GlyGly Arg Lys Pro Lys Arg Lys Met Lys Thr Gln Lys Leu Asp 930 935 940 AlaAsp Leu Leu Val Pro Ala Ser Val Lys Val Leu Arg Arg Ser Asn 945 950 955960 Pro Lys Lys Ile Asp Asp Pro Ile Asp Glu Glu Glu Glu Phe Glu Glu 965970 975 Leu Lys Gly Ser Glu Pro His Met Arg Thr Arg Asn Gln Gly Arg Arg980 985 990 Thr Ala Phe Tyr Asn Glu Asp Asp Ser Glu Glu Glu Gln Arg GlnLeu 995 1000 1005 Leu Phe Glu Asp Thr Ser Leu Thr Phe Gly Thr Ser SerArg Gly 1010 1015 1020 Arg Val Arg Lys Leu Thr Glu Lys Ala Lys Ala AsnLeu Ile Gly 1025 1030 1035 Trp 76 3860 DNA Mus musculus 76 ggacagcagatgctggaatt aacttgcagc caccaaagcc cgttcctcct aagcataaaa 60 ccaagaaaccagaaagtagt tcagatgaag aagaagaatc tgaaaaccag aagcaaaaac 120 atattaaaaaggaaagaaaa aaagcaaatg aagaaaaaga tggaccaaca tcaccaaaga 180 aaaaaaaagcccaaagaaag aaaacaaaag agattggctg taggagaact aactgagaat 240 ggcctaacgttagaagagtg gttgccttca gcttggatta cagacacact tcccaggaga 300 tgtccatttgtgccacagat gggtgatgag gtttattatt ttcgacaagg gcatgaagca 360 tatgttgagatggcccggaa aaataaaatt tatagtatca atcctaaaaa gcagccatgg 420 cataagatggaactaaggga acaagaacta atgaaaattg ttggtataaa gtatgaagtg 480 gggttgcctaccctttgctg ccttaaactt gcttttctag atcctgatac tggcaaactg 540 accggtggatcatttaccat gaaataccat gatatgcctg acgtcataga ttttctagtc 600 ttgagacaacaatttgatga tgcaaagtat agacgatgga atataggtga ccgcttcaga 660 tctgtcatagatgatgcctg gtggtttgga acaattgaaa gtcaagagcc tcttcaacct 720 gagtaccctgatagtttgtt tcagtgttat aatgtatgtt gggacaatgg agatacagaa 780 aagatgagtccttgggatat ggaattaata cctaataatg ctgtctttcc agaagaactg 840 ggtaccagtgttcctttaac tgatgttgaa tgtaggtcgc taatttataa acctcttgat 900 ggagattggggagccaatcc cagggatgaa gaatgtgaaa gaattgttgg aggaataaat 960 cagctgatgacactagatat tgcgtctgca tttgttgccc ctgtggacct tcaagcttat 1020 cccatgtattgcactgtggt ggcctatcca acggatctaa gtacaattaa acaaagactg 1080 gagaacaggttttacaggcg cttttcatca ctaatgtggg aagttcgata tatagaacat 1140 aatacacgaacattcaatga gccaggaagc ccaattgtga aatctgctaa atttgtgact 1200 gatcttctcctgcattttat aaaggatcag acttgttata acataattcc actttacaac 1260 tcaatgaagaagaaagtttt gtctgactct gaggaagaag agaaagatgc tgatgttcca 1320 gggacttctaccagaaagcg caaggatcat caacctagaa gaaggttacg caacagagct 1380 cagtcttacgatattcaggc atggaagaaa caatgtcaag aattactgaa tctcatattt 1440 caatgtgaagactcagaacc ttttcgacag ccagtggatc ttcttgaata tccagactac 1500 cgagacatcattgacactcc aatggacttt gccactgtta gagagacttt agaggctggg 1560 aattatgagtcacccatgga gttatgtaaa gatgtcaggc tcattttcag taattctaaa 1620 gcatacacaccaagcaagag atcaaggatt tacagcatga gtttacgcct gtctgctttc 1680 tttgaagaacatattagttc agttttgtca gattataaat ctgctcttcg ttttcataaa 1740 agaaacaccataagcaagaa gaggaagaag cgaaacagga gcagctccct gtccagcagt 1800 gctgcctcaagccctgaaag gaaaaaaagg atcttaaaac cccagctaaa gtcagaagta 1860 tctacctctccattctccat acctacaaga tcagtactac caagacataa tgctgcacaa 1920 atgaatggtaaaccagaatc cagttctgtg gttcgaacta ggagcaaccg tgtagctgta 1980 gatccagttgtcaccgagca gccctctaca tcatcagcca caaaagcttt tgtttcaaaa 2040 actaatacatctgccatgcc aggaaaagca atgctagaga attctgtgag acattccaaa 2100 gccttgagcacactttccag ccctgatccg ctcacattca gccatgctac aaagaataat 2160 tctgcaaaagaaaacatgga aaaggaaaag cctgtcaaac gtaaaatgaa gtcttctgtg 2220 ttttcaaaagcatctccact tccaaagtca gccgcagtca tagagcaagg agagtgtaag 2280 aacaatgttcttataccagg aaccattcaa gtaaatggcc atggaggaca accatcaaaa 2340 ctcgtgaagagaggacctgg gaggaagccc aaggtagaag ttaacaccag cagtggtgaa 2400 gtgacacacaagaaaagagg tagaaagccc aagaatctgc agtgtgcaaa gcaggaaaac 2460 tctgagcaaaataacatgca tcccatcagg gctgacgtgc ttccttcttc aacatgcaac 2520 ttcctttctgaaactaatgc tgtcaaggag gatttgttac agaaaaagag tcgtggaggc 2580 agaaaacccaaaaggaagat gaaaactcac aacctagatt cagaactcat agttcctaca 2640 aatgttaaagtgttaaggag aagtaaccgg aaaaaaacag atgatcctat agatgaggaa 2700 gaggagtttgaagaactcaa aggctctgag cctcacatga gaactagaaa tcagggtcga 2760 aggacaactttctataatga ggatgactcc gaggaagaac agagacagct gttgttcgag 2820 gacacctccttgacatttgg aacttctagt agaggacgag tccgaaagtt gactgaaaaa 2880 gcaaaggctaatttaattgg ttggtaactt gaagcaaaat attgcatttt aaaaaatctg 2940 taacgcaggtacagttaagg agtaagtaga actaaggtct ctgcttcctt gctgctatga 3000 cggattagggaatgttacaa tttgacttgg gaaaatggac aaaaacacat ttagaagata 3060 atttacatctttgaatgaaa aaaatctata tacatatata tttcaaatgt ttgctattta 3120 ttgcccttaggtaggttatt cggttccaca ttcatttcat ttgctgtttg aaattgagga 3180 cctgttataaattctggttt atttatggaa gagacagctc tgctacacta ttaagaaaca 3240 tagtattcctagagataaag tatgttccct cttaaattga gttatttttg accaagtgag 3300 gtacatttttactgatagca gaaggcatgc cctaggaaga gagatgttac aaagagtagc 3360 agtacattaagaatggcttc ctctaaagat aactttccag ttcccaccat ttggtatcct 3420 gaaaagtgttgtgaactgta ggtgttcaat tacagaatat ctagaggaag cttttgtttt 3480 actccatttctgccaaactt aggagaaaaa tgtattgatg caaaggaaac atatccacat 3540 tggaaaacatttgactgtct aatttttcag accttgattc ttatatcagt cactctatct 3600 ctgtttattgtgccaaagac tgagaatcag tgcagtggaa agcctgtttt tgactgtcag 3660 gacagcatacacttttcagt actggaaaag ctatatattc taaagagcaa gttattacaa 3720 aattatgctgagttatatcc tttttttggt actaaatgta ggaaaataat gcactggtgg 3780 gtcctttgacagagatatct tagagaaaaa aaaaaaaaag gaattcgata tcaagcttat 3840 cgataccgtcgacctcgagg 3860 77 968 PRT Mus musculus 77 Gly Gln Gln Met Leu Glu LeuThr Cys Ser His Gln Ser Pro Phe Leu 1 5 10 15 Leu Ser Ile Lys Pro ArgAsn Gln Lys Val Val Gln Met Lys Lys Lys 20 25 30 Asn Leu Lys Thr Arg SerLys Asn Ile Leu Lys Arg Lys Glu Lys Lys 35 40 45 Gln Met Lys Lys Lys MetAsp Gln His His Gln Arg Lys Lys Lys Pro 50 55 60 Lys Glu Arg Lys Gln LysArg Leu Ala Val Gly Glu Leu Thr Glu Asn 65 70 75 80 Gly Leu Thr Leu GluGlu Trp Leu Pro Ser Ala Trp Ile Thr Asp Thr 85 90 95 Leu Pro Arg Arg CysPro Phe Val Pro Gln Met Gly Asp Glu Val Tyr 100 105 110 Tyr Phe Arg GlnGly His Glu Ala Tyr Val Glu Met Ala Arg Lys Asn 115 120 125 Lys Ile TyrSer Ile Asn Pro Lys Lys Gln Pro Trp His Lys Met Glu 130 135 140 Leu ArgGlu Gln Glu Leu Met Lys Ile Val Gly Ile Lys Tyr Glu Val 145 150 155 160Gly Leu Pro Thr Leu Cys Cys Leu Lys Leu Ala Phe Leu Asp Pro Asp 165 170175 Thr Gly Lys Leu Thr Gly Gly Ser Phe Thr Met Lys Tyr His Asp Met 180185 190 Pro Asp Val Ile Asp Phe Leu Val Leu Arg Gln Gln Phe Asp Asp Ala195 200 205 Lys Tyr Arg Arg Trp Asn Ile Gly Asp Arg Phe Arg Ser Val IleAsp 210 215 220 Asp Ala Trp Trp Phe Gly Thr Ile Glu Ser Gln Glu Pro LeuGln Pro 225 230 235 240 Glu Tyr Pro Asp Ser Leu Phe Gln Cys Tyr Asn ValCys Trp Asp Asn 245 250 255 Gly Asp Thr Glu Lys Met Ser Pro Trp Asp MetGlu Leu Ile Pro Asn 260 265 270 Asn Ala Val Phe Pro Glu Glu Leu Gly ThrSer Val Pro Leu Thr Asp 275 280 285 Val Glu Cys Arg Ser Leu Ile Tyr LysPro Leu Asp Gly Asp Trp Gly 290 295 300 Ala Asn Pro Arg Asp Glu Glu CysGlu Arg Ile Val Gly Gly Ile Asn 305 310 315 320 Gln Leu Met Thr Leu AspIle Ala Ser Ala Phe Val Ala Pro Val Asp 325 330 335 Leu Gln Ala Tyr ProMet Tyr Cys Thr Val Val Ala Tyr Pro Thr Asp 340 345 350 Leu Ser Thr IleLys Gln Arg Leu Glu Asn Arg Phe Tyr Arg Arg Phe 355 360 365 Ser Ser LeuMet Trp Glu Val Arg Tyr Ile Glu His Asn Thr Arg Thr 370 375 380 Phe AsnGlu Pro Gly Ser Pro Ile Val Lys Ser Ala Lys Phe Val Thr 385 390 395 400Asp Leu Leu Leu His Phe Ile Lys Asp Gln Thr Cys Tyr Asn Ile Ile 405 410415 Pro Leu Tyr Asn Ser Met Lys Lys Lys Val Leu Ser Asp Ser Glu Glu 420425 430 Glu Glu Lys Asp Ala Asp Val Pro Gly Thr Ser Thr Arg Lys Arg Lys435 440 445 Asp His Gln Pro Arg Arg Arg Leu Arg Asn Arg Ala Gln Ser TyrAsp 450 455 460 Ile Gln Ala Trp Lys Lys Gln Cys Gln Glu Leu Leu Asn LeuIle Phe 465 470 475 480 Gln Cys Glu Asp Ser Glu Pro Phe Arg Gln Pro ValAsp Leu Leu Glu 485 490 495 Tyr Pro Asp Tyr Arg Asp Ile Ile Asp Thr ProMet Asp Phe Ala Thr 500 505 510 Val Arg Glu Thr Leu Glu Ala Gly Asn TyrGlu Ser Pro Met Glu Leu 515 520 525 Cys Lys Asp Val Arg Leu Ile Phe SerAsn Ser Lys Ala Tyr Thr Pro 530 535 540 Ser Lys Arg Ser Arg Ile Tyr SerMet Ser Leu Arg Leu Ser Ala Phe 545 550 555 560 Phe Glu Glu His Ile SerSer Val Leu Ser Asp Tyr Lys Ser Ala Leu 565 570 575 Arg Phe His Lys ArgAsn Thr Ile Ser Lys Lys Arg Lys Lys Arg Asn 580 585 590 Arg Ser Ser SerLeu Ser Ser Ser Ala Ala Ser Ser Pro Glu Arg Lys 595 600 605 Lys Arg IleLeu Lys Pro Gln Leu Lys Ser Glu Val Ser Thr Ser Pro 610 615 620 Phe SerIle Pro Thr Arg Ser Val Leu Pro Arg His Asn Ala Ala Gln 625 630 635 640Met Asn Gly Lys Pro Glu Ser Ser Ser Val Val Arg Thr Arg Ser Asn 645 650655 Arg Val Ala Val Asp Pro Val Val Thr Glu Gln Pro Ser Thr Ser Ser 660665 670 Ala Thr Lys Ala Phe Val Ser Lys Thr Asn Thr Ser Ala Met Pro Gly675 680 685 Lys Ala Met Leu Glu Asn Ser Val Arg His Ser Lys Ala Leu SerThr 690 695 700 Leu Ser Ser Pro Asp Pro Leu Thr Phe Ser His Ala Thr LysAsn Asn 705 710 715 720 Ser Ala Lys Glu Asn Met Glu Lys Glu Lys Pro ValLys Arg Lys Met 725 730 735 Lys Ser Ser Val Phe Ser Lys Ala Ser Pro LeuPro Lys Ser Ala Ala 740 745 750 Val Ile Glu Gln Gly Glu Cys Lys Asn AsnVal Leu Ile Pro Gly Thr 755 760 765 Ile Gln Val Asn Gly His Gly Gly GlnPro Ser Lys Leu Val Lys Arg 770 775 780 Gly Pro Gly Arg Lys Pro Lys ValGlu Val Asn Thr Ser Ser Gly Glu 785 790 795 800 Val Thr His Lys Lys ArgGly Arg Lys Pro Lys Asn Leu Gln Cys Ala 805 810 815 Lys Gln Glu Asn SerGlu Gln Asn Asn Met His Pro Ile Arg Ala Asp 820 825 830 Val Leu Pro SerSer Thr Cys Asn Phe Leu Ser Glu Thr Asn Ala Val 835 840 845 Lys Glu AspLeu Leu Gln Lys Lys Ser Arg Gly Gly Arg Lys Pro Lys 850 855 860 Arg LysMet Lys Thr His Asn Leu Asp Ser Glu Leu Ile Val Pro Thr 865 870 875 880Asn Val Lys Val Leu Arg Arg Ser Asn Arg Lys Lys Thr Asp Asp Pro 885 890895 Ile Asp Glu Glu Glu Glu Phe Glu Glu Leu Lys Gly Ser Glu Pro His 900905 910 Met Arg Thr Arg Asn Gln Gly Arg Arg Thr Thr Phe Tyr Asn Glu Asp915 920 925 Asp Ser Glu Glu Glu Gln Arg Gln Leu Leu Phe Glu Asp Thr SerLeu 930 935 940 Thr Phe Gly Thr Ser Ser Arg Gly Arg Val Arg Lys Leu ThrGlu Lys 945 950 955 960 Ala Lys Ala Asn Leu Ile Gly Trp 965

We claim:
 1. An isolated Pleckstrin Homology domain Interacting Protein(“PHI Protein”) that recruits proteins of the IRS protein family andSTAT transcription factors to receptors that interact with, andphosphorylate the proteins and STAT transcription factors.
 2. Anisolated Pleckstrin Homology domain Interacting Protein (“PHI Protein”)according to claim 1 characterized by an N-terminal α-helix regionpredicting a coiled coil structure and a region containing twobromodomains, which is capable of interacting with a PH domain ofinsulin receptor substrate-1.
 3. An isolated protein as claimed in claim1 or 2 comprising an amino acid sequence of SEQ.ID.NO. 2, 3, 5, 6, 8,10, 12, 13, 15, or
 17. 4. An isolated nucleic acid molecule comprisingat least 30 nucleotides which hybridizes to one of SEQ ID NO. 1, 4, 7,9, 11, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, or 34 or the complement of SEQ ID NO. 1, 4, 7, 9, 11, 14, 16,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34,under stringent hybridization conditions.
 5. An isolated nucleic acidmolecule which comprises: (i) a nucleic acid sequence encoding a proteinhaving substantial sequence identity with the amino acid sequence ofSEQ. ID. NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17; (ii) a nucleic acidsequence complementary to (i); (iii) a nucleic acid sequence differingfrom any of (i) or (ii) in codon sequences due to the degeneracy of thegenetic code; (iv) a nucleic acid sequence comprising at least 10,preferably at least 15, more preferably at least 18, most preferably atleast 20 nucleotides capable of hybridizing to a nucleic acid sequenceof SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, or 34 or to a degenerate form thereof;(v) a nucleic acid sequence encoding a truncation, an analog, an allelicor species variation of a protein comprising the amino acid sequence ofSEQ. ID. NO. 2, 3, 5, 6, 8, 10, 12, 13, 15, or 17; or (vi) a fragment,or allelic or species variation of (i), (ii) or (iii).
 6. An isolatednucleic acid molecule comprises: (i) a nucleic acid sequence havingsubstantial sequence identity or sequence similarity with a nucleic acidsequence of SEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34; (ii) nucleic acidsequences comprising the sequence of SEQ. ID. NO. 1, 4, 7, 9, 11, 14,16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or34 wherein T can also be U; (iii) nucleic acid sequences complementaryto (i), preferably complementary to the full nucleic acid sequence ofSEQ. ID. NO. 1, 4, 7, 9, 11, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, or 34; (iv) nucleic acid sequences differingfrom any of the nucleic acid sequences of (i), (ii), or (iii) in codonsequences due to the degeneracy of the genetic code; or (v) a fragment,or allelic or species variation of (i), (ii) or (iii).
 7. An isolatednucleic acid molecule which encodes a protein which binds an antibody ofa protein as claimed in claim 1, 2 or
 3. 8. A regulatory sequence of anisolated nucleic acid molecule as claimed in any one of claims 4 to 7fused to a nucleic acid which encodes a heterologous protein.
 9. Avector comprising a nucleic acid molecule of any one of claims 4 to 7.10. A host cell comprising a nucleic acid molecule of any one of claims4 to
 7. 11. An isolated protein as claimed in claim 1, 2 or 3 comprisingan amino acid sequence of SEQ. ID. NO. 2,3,5 or
 6. 12. An isolatedprotein as claimed in claim 1 or 2 having at least 65% amino acidsequence identity to an amino acid sequence of SEQ. ID. NO. 2, 3, 5, or6.
 13. A method for preparing a protein as claimed in claim 1comprising: (a) transferring a vector as claimed in claim 9 into a hostcell; (b) selecting transformed host cells from untransformed hostcells; (c) culturing a selected transformed host cell under conditionswhich allow expression of the protein; and (d) isolating the protein.14. A protein prepared in accordance with the method of claim
 13. 15. Abinding region of a protein as claimed in any one of claims 1 to 3, 11,12 or 14 which is a PH domain binding region, an IR binding region, or aSTAT binding region.
 16. A complex comprising a protein as claimed inclaim 1 to 3, 11, 12 or 14 or a binding region thereof, and a bindingpartner.
 17. A complex as claimed in claim 16 wherein the bindingpartner is a PH domain containing protein, a PH domain, a receptor thatinteracts with a protein of the IRS protein family or a binding regionthereof that interacts with the PHI Protein, or a STAT transcriptionfactor or a binding region thereof that interacts with the PHI Protein.18. An antibody having specificity against an epitope of a protein asclaimed in any one of claims 1 to 3, 11, 12 or
 14. 19. An antibody asclaimed in claim 18 labeled with a detectable substance and used todetect the polypeptide in biological samples, tissues, and cells.
 20. Aprobe comprising a sequence encoding a protein as claimed in any one ofclaims 1 to 3, 11, 12 or 14, or a part thereof.
 21. A method ofdiagnosing and monitoring conditions mediated by a protein as claimed inany one of claims 1 to 3, 11, 12 or 14 by determining the presence of anucleic acid molecule as claimed in any one of claims 4 to 8 or apolypeptide as claimed in any one of claims 1 to 3, 11, 12 or
 14. 22. Amethod as claimed in claim 21 wherein the condition is associated withan insulin response, or is cancer.
 23. A method for identifying asubstance which interacts with a protein as claimed in claim 1 to 3, 11,12 or 14 comprising (a) reacting the protein with at least one substancewhich potentially can associate with the protein, under conditions whichpermit the association between the substance and protein, and (b)removing or detecting protein associated with the substance, whereindetection of associated protein and substance indicates the substanceassociates with the protein.
 24. A method for evaluating a compound forits ability to modulate the biological activity of a protein as claimedin claim 1 to 3, 11, 12 or 14 comprising reacting the protein with asubstance that interacts with the protein and a test compound underconditions which permit the formation of complexes between the substanceand protein, and removing and/or detecting complexes.
 25. A method foridentifying inhibitors of a PHI Protein interaction, comprising (a)providing a reaction mixture including a PHI Protein and a bindingpartner, or at least a portion of each which interact; (b) contactingthe reaction mixture with one or more test compounds; and (c)identifying compounds which inhibit the interaction of the PHI Proteinand binding partner.
 26. A method for detecting a nucleic acid moleculeencoding a protein comprising an amino acid sequence of SEQ. ID. NO. 2,3, 5, or 6 in a biological sample comprising the steps of: (a)hybridizing a nucleic acid molecule of any one of claims 4 to 7 tonucleic acids of the biological sample, thereby forming a hybridizationcomplex; and (b) detecting the hybridization complex wherein thepresence of the hybridization complex correlates with the presence of anucleic acid molecule encoding the protein in the biological sample. 27.A method as claimed in claim 26 wherein nucleic acids of the biologicalsample are amplified by the polymerase chain reaction prior to thehybridizing step.
 28. A method for treating a condition mediated by aprotein as claimed in claim 1 to 3, 11, 12 or 14 comprisingadministering an effective amount of an antibody as claimed in claim 18or a substance, compound, or inhibitor identified in accordance with amethod claimed in claim 23, 24, or
 25. 29. A method as claimed in claim28 wherein the condition is associated with an insulin response, or iscancer.
 30. A composition comprising one or more of a nucleic acidmolecule as claimed in any one of claims 4 to 7 or protein claimed inany one of claims 1 to 3, 11, 12 or 14, or a substance or compoundidentified using a method as claimed in any preceding claim, and apharmaceutically acceptable carrier, excipient or diluent.
 31. Use ofone or more of a nucleic acid molecule as claimed in any one of claims 4to 7 or protein claimed in any one of claims 1 to 3, 11, 12 or 14, or asubstance or compound identified using a method as claimed in anypreceding claim in the preparation of a medicament for treating acondition mediated by a protein as claimed in claim
 1. 32. A transgenicnon-human mammal which doe not express a PHI Protein as claimed in claim1 to 3, 11, 12 or 14 resulting in a PHI Protein associated pathology.33. A transgenic animal assay system which provides a model system fortesting for an agent that reduces or inhibits a PHI Protein associatedpathology comprising (a) administering the agent to a transgenicnon-human animal as claimed in claim 32; and (b) determining whethersaid agent reduces or inhibits a PHI Protein associated pathology in thetransgenic non-human animal relative to a transgenic non-human animal ofstep (a) which has not been administered the agent.
 34. A method ofconducting a drug discovery business comprising: (a) providing one ormore assay systems for identifying agents by their ability to inhibit orpotentiate the interaction of a protein as claimed in any precedingclaim and a binding partner; (b) conducting therapeutic profiling ofagents identified in step (a), or further analogs thereof, for efficacyand toxicity in animals; and (c) formulating a pharmaceuticalcomposition including one or more agents identified in step (b) ashaving an acceptable therapeutic profile.
 35. A method as claimed inclaim 34 further comprising establishing a distribution system fordistributing the pharmaceutical composition for sale, and optionallyestablishing a sales group for marketing the pharmaceutical preparation.36. A method of conducting a target discovery business comprising: (a)providing one or more assay systems for identifying agents by theirability to inhibit or potentiate the interaction of a protein as claimedin any preceding claim and a binding partner; (b) optionally conductingtherapeutic profiling of agents identified in step (a) for efficacy andtoxicity in animals; and (c) licensing, to a third party, the rights forfurther drug development and/or sales for agents identified in step (a),or analogs thereof.
 37. An isolated nucleic acid molecule comprises: (i)a nucleic acid sequence having substantial sequence identity or sequencesimilarity with a nucleic acid sequence of one of SEQ. ID. NO. 35, and39 through 63; (ii) nucleic acid sequences comprising the sequence ofone of SEQ. ID. NO. 35, and 39 through 63, wherein T can also be U;(iii) nucleic acid sequences complementary to (i), preferablycomplementary to the full nucleic acid sequence of one of SEQ. ID. NO.35, and 39 through 63; (iv) nucleic acid sequences differing from any ofthe nucleic acid sequences of (i), (ii), or (iii) in codon sequences dueto the degeneracy of the genetic code; or (v) a fragment, or allelic orspecies variation of (i), (ii) or (iii).
 38. An isolated neuronaldifferentiation-related protein encoded by: (a) a nucleic acid moleculecomprising one of SEQ ID NO. 39 through 63; or (b) a nucleic acidmolecule encoding a protein comprising SEQ ID NO: 36.